Combination of Raman Spectroscopy and Mass Spectrometry for

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Combination of Raman spectroscopy and mass spectrometry for online chemical analysis Anil Kumar Meher, and Yu-Chie Chen Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.6b02152 • Publication Date (Web): 30 Aug 2016 Downloaded from http://pubs.acs.org on August 31, 2016

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Analytical Chemistry

Combination of Raman Spectroscopy and Mass Spectrometry for Online Chemical Analysis Anil Kumar Meher and Yu-Chie Chen* Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300, Taiwan

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Corresponding author E-mail: [email protected] Fax: +886-3-5723764 Phone: +886-3-5131527

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Abstract Mass spectrometry (MS) and Raman spectroscopy are complementary analytical techniques used to provide information related to chemical structures and functional groups of target analytes. Each instrument provides specific chemical information. If these two analytical tools are coupled on-line, comprehensive structural information can be simultaneously collected from the analytes of interest without losing any important chemical information. Nevertheless, exploring a suitable interface for coupling of these analytical tools, which are governed with different operation principles, remains challenging. In this study, we used a small piece of tissue paper as interface for hyphenating a Raman spectroscope and a mass spectrometer on-line. The paper played multi-roles as sample loading substrate and an emitter to generate electrospray. Furthermore, it can facilitate surface-enhanced Raman spectroscopic analysis to improve analyte signals in Raman spectra. A sample droplet was placed on the tissue paper located close to the laser of the Raman spectroscope and the inlet of mass spectrometer. Raman spectra were first collected by the Raman spectroscope through laser irradiation followed by generation of electrospray on the edge of the paper for MS analysis. Positional isomers were used as model samples to demonstrate the effectiveness of the hyphenated analytical tool in distinguishing isomers. The feasibility of using this Raman-MS hyphenated technique for monitoring chemical reactions on-line in real time was also investigated.

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Introduction Hyphenating of several analytical techniques1-6 is helpful to obtain comprehensive analytical information of target analytes from a single run. The main advantages of using hyphenated techniques in chemical analysis include low consumption of samples and reduction of the possibility of losing important analytical information. Mass spectrometry (MS) is a detection method used to obtain molecular weights and structural information. Raman spectroscopy can provide molecular fingerprint profiles and functional group information.1,2 Although MS is usually used to make final confirmation of analytes of interest, chemical information provided by Raman spectroscopy can facilitate analyte identification. Thus, comprehensive chemical and structural information for analytes of interest can be obtained from the hyphenated technique of MS and Raman spectroscopy. Furthermore, considering if the sample amount is limited in some cases, it is desirable to have complete chemical information from one run using the hyphenated Raman-MS technique. Hyphenating these two analytical techniques requires the use of an interface that can hold the sample properly and facilitate analysis. Thus, to establish a suitable interface remains challenging. Only few studies3,4,7,8 demonstrated the possibility of coupling Raman spectroscopy with MS. Nijhuis et al.3 combined MS with time-resolved ultraviolet-visible absorption spectroscopy and Raman spectroscopy for catalyst characterization. In this approach, products generated in gas phase were monitored by spectroscopy and then directed to the inlet of a mass spectrometer for MS analysis.3 Another study reported a patented technique that combined Raman spectroscopy with MS for analysis of gas phase samples.4 Williams et al. utilized surface enhanced Raman spectroscopy (SERS) and MS in conjunction for studying reactions on transition metal catalysts.7 In their other work, they studied catalytic activity/selectivity during methanol oxidation on 3



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polycrystalline rhodium using SERS along with MS detection in parallel.8 In both studies, reaction products generated in gas phase were detected by the hyphenated technique. Recently, Valero-Pedraza et al. studied hydrogen thermal desorption from ammonia borane using the hyphenated technique of operando Raman spectroscopy and MS.9 Most of the interfaces used in coupling require several pyrotubes to collect gaseous samples for Raman spectroscopic analysis and to align with the MS inlet for MS analysis. Furthermore, these previous reports mainly focused on analysis of samples in gas phase. Raman spectroscopy is a suitable technique used to analyze aqueous samples because the presence of water in the sample does not suppress the Raman signals of other functional groups. Nevertheless, the feasibility of coupling Raman spectroscopy with MS for analysis of liquid samples has not been reported yet. Some obstacles are encountered when hyphenating Raman spectroscopy and MS for analysis of condensed phase samples. A mass analyzer can only handle gas-phase ions; as such, transforming the samples from condensed phase to gas phase remains a challenge when using MS for detection. With rapid development of ionization techniques in the 21st century,5,6,10,11 conversion of samples from condensed phase to gas phase at atmospheric pressure can be easily performed. Among these ionization techniques, a remarkable ionization method is called paper spray ionization.12-15 A piece of triangular chromatographic or filter paper is used as sample loading substrate and ESI emitter in paper spray ionization.12-15 The paper is placed in proximity to the MS inlet. After application of a small aliquot of solvent to the paper at a high voltage, Taylor cone is formed from the sharp end of the paper toward the MS inlet, and electrospray is then generated. Analyte ions can be readily detected by MS. In our previous study, we presented a paper-based ESI-MS approach with a piece of tissue paper as sample loading substrate and ESI 4


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emitter.16 Taylor cone can be formed from the fine fibers on the tissue paper. Thus, the shape of the paper does not affect the formation of Taylor cone for electrospray generation. Any shapes of paper can be used as emitter in this paper spray approach. Similar observation was also reported by Narayanan et al.17 and Motoyama et al.18 We also found that direct electric contact on the paper is unnecessary when generating electrospray. Hence, electrospray can be produced from the tissue paper as long as the paper is placed very close to the inlet of the mass spectrometer applied with a high voltage. That is, polarization-induced electrospray19 mainly dominates the ionization process in this tissue paper-based ESI approach. Upon application of a microdroplet of sample solution over the paper placed in close (2–3 mm) to the inlet of mass spectrometer applied with a high voltage (–4500 V), ion signals originating from the analytes can be readily recorded by the mass spectrometer. The setup is simple and can be easily operated because electric contact with the paper emitter is not required. On the basis of the tissue paper-based ESIMS approach, we proposed a simple hyphenated method for coupling Raman spectroscopy and MS with a small piece of tissue paper as interface.

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Experimental Section Materials and reagents Retinoic acid, p-hydroxybenzoic acid, 8-hydroxy quinoline, 4-hydroxy quinoline, riboflavin, 1,3-diaminopropane, ammonium hydroxide, and silver nitrate were purchased from Sigma (St. Louis, MO, USA). Salicylic acid was obtained from Chem Service (West Chester, PA, USA). Nicotinic acid and trisodium citrate-2-hydrate were acquired from Riedel-de Haën (Seelze, Germany). Tissue paper was supplied by Kimberly–Clark (Dallas, TX, USA). Glass slides were provided by Matsunami Glass Ind. Ltd. (Kishiwada City, Osaka, Japan). Carbon tape was purchased from Ted Pella Inc. (Redding, CA, USA). Ethanol was obtained from Echo Chemical Co. Ltd. (Miaoli, Taiwan). Instrumentation A micrOTOF Q II mass spectrometer (Bruker Daltonics, Bremen, Germany) was operated at either positive or negative ion mode. The voltage applied on the orifice of the mass spectrometer was −4500 V (positive ion mode) or +4500 V (negative ion mode). The temperature of the capillary for ion transfer was set to 220 °C. The metal extension tube adapted to the orifice of the mass spectrometer possessed a length of ~5 cm and an inner diameter of ~1 mm. Raman spectra were obtained using an assembled Raman spectroscope (Protrustech Co. Ltd., Taipei, Taiwan) equipped with a spectrometer (Andor Technology Ltd., Belfast, UK) and a continuous-wave laser (λ= 532 nm). The total exposure time for signal acquisition was 2 s, and four acquisitions were performed for each spectrum. In reaction monitoring experiments, the acquisition time was 1 s, and two acquisitions were conducted for each spectrum.

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Coupling Raman spectroscopy and MS A small piece of tissue paper with a circular shape (diameter: ~0.6 cm) was placed over a glass slide and adhered with a black carbon tape on the back of the slide. The black background reduced unwanted scattering from the substrate and allowed a firm base for signal acquisition. The tissue paper was placed close to the MS inlet, and the Raman laser was focused on the substrate (Scheme 1). A sample droplet (10 µL) containing analytes was deposited on the same substrate. Both the mass spectrometer and Raman spectroscope were in acquisition mode before sample deposition on the paper. Thus, MS and Raman spectral results could be acquired immediately after sample loading. The samples were prepared in a mixture of ethanol and deionized water (1:1, v/v) unless otherwise stated. The entire Raman spectroscopic setup was mounted on a wheeled cart, which can be easily transported and positioned appropriately with respect to the MS inlet. Synthesis of silver nanoparticles Silver nanoparticles (Ag NPs) were prepared through Turkevich method.20,21 Aqueous AgNO3 (1 mM, 10 mL) was heated to nearly boiling. Trisodium citrate-2-hydrate (10 mg/mL) was added drop wise to the silver nitrate solution as soon as the solution started boiling. The color of the solution slowly turned into grayish yellow, indicating the reduction of Ag+ ions to Ag NPs. Heating was continued for 5 min, and the solution was cooled to room temperature. The generated Ag NP suspension was centrifuged at 10,000 rpm for 10 min and then rinsed with deionized water (1 mL × 2) to remove the unreacted reactants. The resultant Ag NPs were redispersed in deionized water (1 mL). The concentration of Ag NPs in the resultant suspension was estimated to be ~2.9 mg/mL.

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Sample preparation for surface-enhanced Raman spectroscopic analysis Ag NPs were subjected to surface-enhanced Raman spectroscopy (SERS) analysis to enhance the Raman spectra of the analytes, which showed weak spectroscopic signals. Equal volumes (10 µL) of the Ag NP suspension and analyte solution were mixed before sample deposition. The mixture (10 µL) was applied to the paper for dual Raman and MS analyses, as shown in Scheme 1. The interaction between the analytes (salicylic acid and p-hydroxybenzoic acid) and Ag NPs was optimized by alkalizing analytes with addition of aqueous ammonia hydroxide (0.3 %) to obtain a pH of 9 prior to mixing with Ag NPs.

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Results and Discussion

Scheme 1 shows the experimental setup used to hyphenate a Raman spectroscope and a mass spectrometer. A small piece of tissue paper was loaded with a sample droplet (~10 µL). The fine fibers on the paper can facilitate ionization of the sample when placed close to the MS inlet applied with high voltages. Electric contact on the tissue paper was unnecessary. Raman laser was used to irradiate the sample droplet and obtain emission light from the sample right before the sample was converted to gas phase via polarization-induced electrospray. Retinoic acid was initially used as model sample for hyphenation through coupling of Raman spectroscopy and MS by using a piece of tissue paper as interface. After placing a drop of the sample (10 µL) over the paper substrate, signals were acquired immediately by the mass spectrometer and the Raman spectroscope (Figure 1). Figure 1A shows the Raman spectrum of retinoic acid. Intense peaks appeared at 1017, 1162, 1270, 1299, 1343, 1391, and 1579 cm−1. The intense peak at 1579 cm−1 is assigned to C=C stretching.22,23 The peaks at 1270, 1299, 1343, and 1391 cm−1 represent CCH in-plane rocking,22 the peak at 1162 cm−1 is attributed to C-C stretching,22 and the peak at 1017 cm−1 is due to hydrogen out of plane wagging of C-H in the chain.22 Figure 1B shows the resultant mass spectrum obtained from negative ion mode. The mass spectrum was dominated by the ion peak at m/z 299, which is derived from the deprotonated retinoic acid. The inset in Figure 1B shows the MS/MS spectrum, with the peak at m/z 299 as the precursor ion. Apparently, a fragment ion peak at m/z 255 appeared in the mass spectrum. The fragment ion was obtained by losing a CO2 group (inset in Figure 1 B). Supplementary Video 1 shows the spectra of retinoic acid obtained simultaneously from the Raman spectroscope and the mass spectrometer in real time by using the proposed setup. Ion signal at m/z 299 derived from retinoic acid immediately appeared in the mass spectra (top on the left), whereas Raman peaks representing retinoic acid 9



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appeared in the Raman spectra (right) upon sample deposition. These results indicate that a piece of tissue paper can sufficiently function as interface for coupling of the two instruments. The paper can be loaded with a small sample droplet to facilitate sample irradiation by the Raman laser as well as sample ionization for MS analysis. The hyphenated setup is simple and straightforward because only one piece of paper is sufficient for coupling of a Raman spectroscopy and MS. Retinoic acid possesses Raman active functional groups, i.e. alternate double bonds, so desirable Raman spectrum can be easily obtained (Figure 1A). However, not all molecules possess strong Raman active functional groups. Raman spectroscopy may be difficult to use for analysis of certain molecules. Nevertheless, the sensitivity of Raman spectroscopic analysis to certain analytes has been improved up to six orders of magnitude because of the introduction of SERS,24 in which additional Au/Ag NPs were added in the samples.25 The proposed approach is simple and allows incorporation of Ag/Au NPs in the sample preparation. Hence, samples were mixed with Ag NPs prior to sample deposition. Figure 2A shows the resultant SERS spectrum (red curve) of sample obtained from mixing nicotinic acid with Ag NPs. The intense peak at 1034 cm−1 is due to trigonal ring breathing mode.26 The peaks at 845 and 1598 cm−1 are attributed to ring vibration of nicotinic acid.26 Peak at 1389 cm−1 is assigned to symmetric stretching mode of the COO- group.26 In the absence of Ag NPs in the sample, the Raman spectrum of the same nicotinic acid sample showed a weak peak at 1034 cm−1 (black curve, Figure 2A). The corresponding mass spectrum of nicotinic acid was dominated by the intense peak at m/z 122, which is derived from deprotonated nicotinic acid (Figure 2B). Supplementary Video 2 shows the online signal acquisition for nicotinic acid by using the Raman spectroscope

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and the mass spectrometer in the proposed setup. The spectra from Raman spectroscopy and MS were obtained immediately right after the sample deposition on the interface paper. Nevertheless, one may suspect that the presence of Ag NPs and the Raman laser in the current approach may affect the resultant mass spectra. Thus, we examined the mass spectra of nicotinic acid in the presence of these factors. Figures S1A and S1B show the PI-ESI mass spectra of nicotinic acid ([M+H]+= 122) obtained without and with the presence of Ag NPs in the samples. The protonated molecular ion of nicotinic acid at m/z 122 dominated the mass spectra. There was no much difference between these two mass spectra. No any ion signals derived from silver ions (e.g. m/z 107 and 109) were observed in the mass spectra. Figure S1C shows the PIESI mass spectrum of nicotinic acid obtained with the irradiation of a Raman laser. The mass spectrum looked similar to those shown in Figures S1A and S1B although fewer background ions were observed. The results indicated that the presence of Ag NPs and the Raman laser does not affect mass spectral results apparently. In addition, fluorescent molecules exhibit low signals in Raman spectra. Thus, we used a fluorescent molecule, i.e. riboflavin, as model sample to demonstrate the feasibility of combining SERS with MS. Figure 2C shows the Raman (black curve) and SERS spectra (red curve) of riboflavin from the hyphenated instrument. No apparent peaks appeared in the Raman spectrum (black curve) because of the fluorescence effect. However, the Raman fingerprint spectrum of riboflavin started to appear (red curve) upon mixing of analytes with Ag NPs in the sample. The Raman spectrum of riboflavin was dominated by bands at 1349 and 1630 cm− １ , which correspond to C-N and C-C stretching modes, respectively.27 Moreover, the mass spectrum of riboflavin was immediately obtained. The spectrum was dominated by peaks at m/z 377 and m/z 399, which are attributed to the protonated molecule and sodium adducts of riboflavin, 11



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respectively (Figure 2D). The results indicated that the proposed setup is suitable for coupling of SERS with MS, simply using a small piece of paper as interface. To further explore the practical applications of the setup, we used positional isomers, i.e. 8hydroxyquinoline and 4-hydroxyquinoline as model samples. Positional isomers exhibit the same molecular weights and may also show similar fragment patterns in the MS/MS spectra. Raman spectroscopy can be used to provide fingerprint profiles for differentiating positional isomers. Figures 3A and 3B show the mass spectra of 8-hydroxyquinoline and 4-hydroxyquinoline, respectively. These spectra were dominated by peak at m/z 146, which is due to the protonated molecule of the positional isomers. Collision energy of 25 eV was applied to the collision cell for MS/MS analysis of 8-hydroxyquinoline (Figure 3C) and 4-hydroxyquinoline (Figure 3D), with the peak at m/z 146 as the precursor ions. Prominent product ions appeared at m/z 102, 117, and 128 in the resultant MS/MS spectra. The mass spectrum in Figure 3C resembles the mass spectrum shown in Figure 3D. Thus, distinguishing these two isomers based on their corresponding MS and MS/MS results is difficult. Figure 3E shows the SERS spectra of 8hydroxyquinoline (red curve) and 4-hydroxyquinoline (black curve) obtained from the proposed hyphenated analytical tool on-line. The two analytes were fluorescent compounds; thus, Ag NPs were added to the samples prior to deposition on the tissue paper for Raman spectroscopic and MS analysis. Apparently, the appearance of the two Raman spectra differed. Hence, the two positional isomers can be differentiated based on their Raman spectral profiles. The characteristic band at 495 cm−1 was absent in the Raman spectrum of 4-hydroxyquinoline, whereas the bands at 1362 and 1565 cm−1 were prominent in the Raman spectrum of 8hydroxyquinoline. Hence, coupling Raman spectroscopy with MS can be used to differentiate 8hydroxyquinoine and 4-hydroxyquinoline in a single run. Analytical results including molecular 12


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weights, chemical structures, and functional groups can be readily obtained by using the hyphenated technique. Another pair of isomers, i.e. salicylic acid and p-hydroxy benzoic acid, was used as model sample to demonstrate the feasibility of the hyphenated technique in differentiating positional isomers. Figures 4A and 4B show the mass spectra of salicylic acid and p-hydroxybenzoic acid, respectively. The mass spectra were dominated by the peak of protonated molecule at m/z 137. Figures 4C and 4D show the MS/MS spectra obtained by selecting the ion at m/z 137 as the precursor ion. The resultant MS/MS spectra were dominated by the product ion peak at m/z 93, which represents the loss of CO2 from deprotonated molecule. Thus, distinguishing these two positional isomers based on the results obtained from MS and MS/MS is difficult. Figure 4E shows the SERS spectra of salicylic acid (black curve) and p-hydroxybenzoic acid (red curve) obtained using the hyphenated technique on-line. The Raman spectral profiles obtained from the two analytes differed. The peaks at 812, 1038, 1251, 1279, 1379, and 1617 cm−1 appeared in the Raman spectrum of salicylic acid, whereas peaks at 1038 and 1251 cm−1 in the Raman spectrum of p-hydroxybenzoic acid were missing. The peaks at 1617, 1251, and 1379 cm−1 are attributed to aromatic ring vibration, C-O vibration, and COO- vibration modes, respectively.28 The peak at 232 cm−1 is presumably derived from Ag-O vibration mode.28 The results showed that the hyphenated technique can be used to distinguish salicylic acid from p-hydroxybenzoic acid by using the comprehensive chemical information obtained through Raman spectroscopy and MS in a single run. The current hyphenated technique comprising Raman spectroscopy and MS can be effectively used to obtain chemical information through a single run for few seconds. For further study, we used the proposed system for analysis of a complicated sample. That is, this technique 13



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was used to monitor fast chemical reactions occurring in situ on the interface paper within few seconds. A fast chemical reaction, i.e. Schiff base reaction, which can be carried out within few seconds, was selected as model reaction. Benzaldehyde and 1, 3 diaminopropane were selected as reactants. The hyphenated technique was used to directly acquire time-dependent Raman and mass spectra of the model reaction occurring in situ on the tissue paper. Online mass and Raman spectra were collected simultaneously after deposition of 1,3 diaminopropane (5 µL, MW = 74 Da) to the tissue paper loaded with benzaldehyde solution (5 µL, MW= 106 Da). Figure 5A shows the reaction scheme. The product ion should appear at m/z 163. Figure 5B shows the timeresolved mass spectra obtained starting from addition of 1,3-diaminopropane to benzaldehyde loaded on the tissue paper. Only the peak at m/z 107 initially appeared in the mass spectrum; this peak is derived from protonated benzaldehyde. Upon addition of 1,3-diaminopropane to benzaldehyde on the tissue paper, the peak at m/z 163, which represents the product ion, immediately appeared in the mass spectrum within 1 s. As the monitoring time was extended to 5 s, the peak at m/z 163, which is due to the product, dominated the entire mass spectrum. Figure 5C shows the corresponding Raman spectra acquired simultaneously with MS monitoring. The Raman spectrum of benzaldehyde showed intense bands at 1002 and 1600 cm−1, which correspond to C=C stretching modes.29 The peak at 1704 cm−1 is contributed by carbonyl group in benzaldehyde.29 After the addition of 1,3-diaminopropane to the tissue paper loaded with benzaldehyde, a Raman peak at 1649 cm−1 appeared; this peak represents the stretching vibration mode of an imine group (C=N)30 derived from the reaction product. The peak at 1649 cm−1 became quite apparent within 5 s, whereas the intensity of the peak at 1704 cm−1, which is attributed to C=O stretching mode derived from benzaldehyde, was weakened (Supplementary Video 3) with the passage of time. Apparently, the reaction occurring between benzaldehyde and 14


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1,3 diaminopropane can be readily monitored by Raman spectroscopy and MS simultaneously in the current hyphenated technique. The appearance of the reaction product can also be instantly observed. Hence, the proposed hyphenated technique can be used to effectively monitor fast chemical reactions in real time.

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Conclusions

Although MS is usually used to confirm identity of analytes of interest, the chemical information provided by Raman spectroscopy can be used to further facilitate the confirmation of analytes such as position isomers. In this study, we have demonstrated the use of combined Raman spectroscope and mass spectrometer in a single setup, with a paper substrate as the interface. To the best of our knowledge, this paper is the first to report that condensed phase samples can be analyzed simultaneously by Raman spectroscopy and MS through a hyphenated technique in a single run. Positional isomers and reaction species can be instantly identified using the hyphenated technique on-line in real time. The use of a tissue paper as the interface between Raman spectroscope and mass spectrometer is extremely simple and has no compromises. The micro-capillary nature of the fine fibers on the tissue paper renders this material as a suitable ESI emitter for ionization of analytes. Moreover, the Raman laser can easily irradiate the sample on the tissue paper to obtain Raman spectra. The paper can also be readily used as a suitable SERS sample holder to facilitate the acquiring of improved Raman spectra of the analytes with weak Raman signals. Furthermore, the MS results are not affected in the presence of Ag NPs when combined with SERS. We have demonstrated the effectiveness of using this setup in distinguishing positional isomers. The proposed setup can be used to simultaneously monitor reaction species generated in fast chemical reactions. A small sample volume (5-15 µL) is required for comprehensive analysis, including monitoring of chemical reactions. The hyphenated technique features simplicity, small sample consumption, and fast analysis. We believe that this hyphenated technique could be used for analysis of various samples to obtain comprehensive chemical information.

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Acknowledgements We thank the Ministry of Science and Technology of Taiwan (MOST102-2113-M-009-019MY3) for financial support of this research. AKM thanks NCTU for providing him the International Student Scholarship.

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Supporting Information Additional experimental results. This material is available free of charge via the Internet at http://pubs.acs.org/.

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(15) Damon, D. E.; Davis, K. M.; Moreira, C. R.; Capone, P. C.; Cruttenden, R.; Badu-Tawiah, A. K. Anal. Chem. 2016. (16) Meher, A. K.; Chen, Y.-C. RSC Advances 2015, 5, 94315-94320. (17) Narayanan, R.; Sarkar, D.; Cooks, R. G.; Pradeep, T. Angew. Chem. Int. Ed. 2014, 53, 59365940. (18) Motoyama, A.; Kihara, K. Rapid Commun. Mass Spectrom. 2015, 29, 1905-1916. (19) Meher, A. K.; Chen, Y. C. J. Mass Spectrom. 2015, 50, 444-450. (20) Turkevich, J.; Stevenson, P. C.; Hillier, J. Disc. Faraday Soc. 1951, 11, 55-75. (21) Pillai, Z. S.; Kamat, P. V. J. Phys. Chem. B 2004, 108, 945-951. (22) Morjani, H.; Beljebbar, A.; Sockalingum, G.; Mattioli, T.; Bonnier, D.; Gronemeyer, H.; Manfait, M. Biospectroscopy 1998, 4, 297-302. (23) Ascenso, A.; Guedes, R.; Bernardino, R.; Diogo, H.; Carvalho, F. A.; Santos, N. C.; Silva, A. M.; Marques, H. C. Aaps Pharmscitech 2011, 12, 553-563. (24) Eustis, S.; El-Sayed, M. A. Chem. Soc. Rev. 2006, 35, 209-217. (25) Guo, L.; Jackman, J. A.; Yang, H.-H.; Chen, P.; Cho, N.-J.; Kim, D.-H. Nano Today 2015, 10, 213-239. (26) Barthelmes, J.; Pofahl, G.; Panagiotakis, M.; Plieth, W. J. Raman Spectrosc. 1993, 24, 737743. (27) Liu, F.; Gu, H.; Lin, Y.; Qi, Y.; Dong, X.; Gao, J.; Cai, T. Spectrochim. Acta Mol. Biomol. Spectrosc. 2012, 85, 111-119. (28) Sánchez-Cortés, S.; Garcia-Ramos, J. J. Colloid Interface Sci. 2000, 231, 98-106. (29) Kuiper, A.; Medema, J.; Van Bokhoven, J. J. Catal. 1973, 29, 40-48. (30) Hu, J.; Li, K.; Li, W.; Ma, F.; Guo, Y. Appl. Catal. Gen. 2009, 364, 211-220. 20


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Figure Legends Figure 1. (A) Raman spectrum of retinoic acid (10-3 M) obtained by placing the sample droplet (10 µL) on a tissue paper with a circular shape at a focused distance for the Raman spectroscope (B) The corresponding mass spectrum obtained on-line in negative ion mode from the Raman spectroscopy-MS hyphenated technique. The inset on the left shows the MS/MS spectrum by selecting the ion at m/z 299 as the precursor ion, and the inset on the right shows the possible fragmentation site of retinoic acid. Figure 2. SERS spectrum of (A) nicotinic acid (5 × 10-3 M) and (B) its corresponding mass spectrum obtained on-line from the Raman spectroscopy-MS hyphenated technique by placing a sample droplet (10 µL) that had been mixed with Ag NPs (1.4 mg/mL) on the tissue paper. SERS spectrum of (C) riboflavin (5 × 10-3 M) and (D) its corresponding mass spectrum obtained online from the same hyphenated technique by placing a sample droplet (10 µL) that had been mixed with Ag NPs (1.4 mg/mL) on the tissue paper. Figure 3. Mass spectra of the samples including (A) 8-hydroxyquinoline (5 × 10-3 M) and (B) 4hydroxyquinoline (5 × 10-3 M) obtained by placing the sample droplets (10 µL) containing Ag NPs (1.4 mg/mL) on the tissue paper in the Raman spectroscopy-MS hyphenated setup. (C) (D) Their corresponding MS/MS spectra by selecting the ion at m/z 146 as the precursor ion. The collision energy was set to 25 eV. (E) SERS spectra of 8-hydroxyquinoline (red) and 4hydroxyquinoline (black) obtained on-line from the same setup. Figure 4. Mass spectra of the samples containing (A) salicylic acid (5 × 10-3 M) and (B) phydroxybenzoic acid (5 × 10-3 M) obtained by placing the sample droplet (10 µL) containing Ag NPs (1.4 mg/mL) at pH 9 to the interface paper in the Raman spectroscopy-MS hyphenated 21



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instrument. The corresponding MS/MS spectra of (C) salicylic acid (5 × 10-3 M) and (D) phydroxybenzoic acid (5 × 10-3 M) by selecting the peak at m/z 137 as the precursor ion. The collision energy was set to 20 eV. (E) SERS spectra of salicylic acid (black) and phydroxybenzoic acid (red) that were obtained simultaneously with mass spectra from the hyphenated setup. Figure 5. (A) Reaction scheme occurring between 1,3 diaminopropane and benzaldehyde. Time resolved (B) mass spectra and (C) Raman spectra acquired at an interval of 1 s obtained by monitoring this reaction that occurred in situ on the interface paper of the hyphenated setup in real time. The results were acquired by addition of 1,3 diaminopropane (5 µL, 5.95 M) onto the paper that had been loaded with benzaldehyde (5 µL, 4.85 M).

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Scheme 1. Schematic illustration of the integrated setup of a Raman spectroscope and a mass spectrometer using a piece of tissue paper as the interface.

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Figure 1

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Figure 2

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Figure 3

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Figure 4

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Figure 5

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TOC Graphic


Combination of Raman Spectroscopy and Mass Spectrometry for

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