Illumination of nanoliter-NMR spectroscopy chips for real-time

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Illumination of nanoliter-NMR spectroscopy chips for real-time photochemical reaction monitoring M. Victoria Gomez, ALBERTO JUAN, Francisco Jimenez-Marquez, Antonio de la Hoz, and Aldrik H. Velders Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b04114 • Publication Date (Web): 27 Dec 2017 Downloaded from http://pubs.acs.org on December 29, 2017

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Analytical Chemistry

Illumination of nanoliter-NMR spectroscopy chips for realtime photochemical reaction monitoring. M. Victoria Gómez,*‡ Alberto Juan,‡ Francisco Jiménez-Márquez,Φ Antonio de la Hoz‡ and Aldrik H. Velders.*,‡,ζ ‡

Instituto Regional de Investigación Científica Aplicada (UCLM), Avda Camilo Jose Cela s/n, 13071. Ciudad Real. Spain

Φ

Escuela Técnica Superior de Ingenieros (ETSI) Industriales (UCLM), Avda Camilo Jose Cela s/n, 13071. Ciudad Real. Spain

ζ

Laboratory of BioNanoTechnology, Wageningen University, PO Box 8038, 6700 EK Wageningen, The Netherlands.

ABSTRACT: We report the use of a small-volume nuclear magnetic resonance (NMR) spectroscopy device with integrated fiber-optics for the real-time detection of UV-vis light assisted chemical reactions. An optical fiber is used to guide the light from LEDs or laser diode positioned safely outside the magnet, towards the 25 nL detection volume and placed right above of the microfluidic channel, irradiating the transparent back side of the NMR chip. The setup here presented overcomes the limitations of conventional NMR systems for in situ UV-vis illumination, with the microchannel permitting efficient light penetration even for highly concentrated solutions, requiring lower power light intensities, and enabling high photon flux. The efficacy of the setup is illustrated with two model reactions activated at different wavelengths.

We here report a novel setup for efficient monitoring of light-assisted reactions exploiting small-volume NMR chips. The use of light of a particular energy as “green reagent” in photochemical reactions1 has proven applicability in many different fields. Large-scale photochemistry encounters several difficulties mainly related to the irradiation of optically thick solutions where light penetration is compromised and only absorbed by the first few hundreds of microns. Microphotochemistry eliminates those limitations as the sample is contained within microchannels of reduced depth which enables light to penetrate through most of the reactor depth allowing the sample to absorb uniformly the incident light.2,3,4,5 The reduced dimensions make analysis harsh, so a device for the in situ monitoring of light-assisted reactions in microreactors with a powerful technique like NMR spectroscopy would be of high interest. Integration of in situ UV-vis illumination in conventional NMR spectrometer setups has been explored in applications as photochromics,6 photoisomerizations,7 photocatalysis,8,9,10 and photochemically induced dynamic nuclear polarization,11, 12 among other uses. The common setups for in situ UV-vis illumination deals with an optical fiber13 mounted in a coaxial insert and dipped, so invasively, into a 5 mm NMR tube with hundreds of microliters of sample. Typically encountered problems when attempting to illuminate the whole sample volume uniformly relate to excessive local heating effects, exponential fall in light intensity inside the NMR tube, and magnetic field distortions, among others.14,15,16,17 More recently, Gschwind et al.18,19 reported a pulsed operation LED based illumination setup for a 5 mm-NMR tube, showing the advantages of the combination of the LEDs to an optical fiber and the need of illumination of the whole NMR sample. Here we present an alternative approach for integrated NMR monitoring and illumination setup exploiting small volume NMR chips and non-invasive positioning of the optical fiber close to but outside the nanoliter NMR detection volume.

Figure 1. Schematic of the setup formed by an external light source (A), an optical fiber (B) and a reaction-detection zone (C). It comprises the illumination of a confined volume underneath the microcoil, but also the neighboring microchannel area, preventing concentration gradients to affect the measurements. The distance between the core of the optical fiber and the sample channel is 3 mm. The system is non-invasive with the optical fiber illuminating from outside and irradiating the transparent back side of the NMR chip

In the past decade we have investigated miniaturization of NMR devices20,21,22 showing microfluidic NMR chips with integrated planar spiral transceiver coils to have excellent mass sensitivity for analysis of samples with detection volumes in the lower nanoliter range.23,,24 Such chips can readily be hyphenated to e.g. microwave irradiation or conventional thermal heating sources, allowing rapid in-line reaction monitoring of non-isothermal and isothermal processes, respectively.25,26 We recognized that the high surface to volume ratio of the NMR chips could offer the ideal scenario for in situ monitoring of photochemical reactions, as the low volume within the channels of the microreactor does not require complex or high power illumination devices. We

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present a novel setup for the uniform illumination of nanolitre samples with two different low power light sources, for the in situ NMR analysis of UV-vis-assisted chemical reactions (Figure 1). The photocatalytic reductive dehalogenation of αbromoacetophenone3 shows the efficiency of the setup when LEDs are used. The photochemical transformation of onitrobenzaldehyde to o-nitrosobenzoic acid27 was employed as model reaction to illustrate the limitation of LEDs and the alternative use of a laser diode.

EXPERIMENTAL SECTION Custom-built light source. Light-Emitted Diodes (LEDs) (Figure S1): The PCB with 28 bulbs that operate in continuous wave was fabricated with a PM C100/HF apparatus. The output power per LED unit was 55 kmcd for 525 nm. The LEDs were connected in series in blocks of 6, with a minimum voltage possible (3V per LED) and a resistance of 60 Ω. A hole was made in the center of the PCB to fix a 5 mm diameter optic fiber. The PCB was adjusted into an aluminum box via a rail system on the bottom. A concave mirror (5.08 mm diameter, 50 mm confocal distance, CM50-D50-E02) was placed inside the aluminum box and opposite to the PCB of LEDs to guide the light into the core of an optical fiber (Figure S2, left). The position of the mirror was adjusted by means of a railing system at the bottom of the box to keep the optic fiber at the confocal distance of the mirror. An axial fan (50 x 50 mm, 5000 rpm, 20 m3 h-1) was located inside the aluminum box. Laser diode (LD) (Figure 2): This system consisted of a laser diode DL5146-101S (Thorlabs), with an optical output power of 45 mW and peaks at 405 nm. The laser diode was biased by a driver circuit powered at 24 V. The laser diode power output depends on a variable voltage divider based on a potentiometer which sets the voltage level of Vref and therefore the laser diode current due to the negative feedback of the laser diode driver. A BJT npn transistor with a heat sink, three operational amplifiers (differential, transimpedance and inversor) and some passive components compose the PCB (Figure S2, right). The laser diode, was mounted in a collimation tube (LT220P-B) to focus its light (Figure S3), and a Teflon frame was used to align the focused beam of light into the optical fiber. Nanoliter NMR probe. Nanoliter NMR chips. The NMR chips were made of glass (D263) that show more than 90% transmission of light for the wavelengths used in this work. Microfluidic chips with an NMR detection volume of 25 nL were designed using Clewin Layout Editor (Version 4.4.3.0) and fabricated as described before, and with a customized chip holder to position the chip inside the NMR superconductive magnet.25, 28 The chip holder was placed on top of a sacrificed Varian probe with an additional external variable capacitor (0-3.5 pF) for tuning the microcoil to the 1H resonance frequency. The probe is not equipped with temperature regulation and all experiments were performed in non-locked mode (what contributes to the relatively broader lines observed). An Oxford Instrument 9.4 T narrow bore magnet equipped with a Varian INOVA spectrometer operated at 400 MHz for 1H detection was used to carry out the NMR experiments. Fiber optic. The light from the LED or laser diode is guided towards the rf-microcoil by means of a plastic optical fiber (length, 2 m; diameter, 5 mm, solid core tic end glow with a

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black PVC jacket (Fiber Optic Products Inc)). The diameter of the optical fiber was chosen wider (5 mm) than the inner diameter of the microcoil (250 µm), that defines the active volume, to avoid diffusion of the reactants towards the detection volume of the coil due to concentration gradients generated after light irradiation. An adapter was placed on the customized NMR-chip-holder to fix the fiber optic exactly above the detection volume under the radiofrequency microcoil. A digital handheld laser power meter (PM100D, Thorlabs) was used to measure the amount of light that comes out of the fiber optic at the corresponding wavelength. Around 80-90% of light is lost when adapting the optical fiber to the LED system whilst losses of only 20% were detected when a laser diode was chosen as energy source. General procedure for in situ sample irradiation Photocatalytic reductive dehalogenation of αbromoacetophenone (1). The experimental procedure reported in literature3 was followed: α-bromoacetophenone (1) (1 eq.), Eosin Y (0.025 eq.), diethyl-2,6-dimethyl-1,4dihydropyridine-3,5-dicarboxylate (3) (2 eq.) and DIPEA (2 eq.) were mixed in an Schlenk using DMF as solvent (Scheme 1). The concentration of α-bromoacetophenone (1) was 0.5 M. The mixture was degassed with argon and was transferred to the syringe that was used to fill the NMR chip. Consecutive NMR experiments were launched on a stopped-flow sample starting when LEDs were switched on (525 nm). The NMR acquisition parameters defined a total experiment time of 54 s (90 pulse of 7 µs, acquisition time of 0.2 s, preacquisition delay of 0.05 s, number of scans was 216). Complete reaction conversion was achieved after 8 min of irradiation. Photochemical transformation of o-nitrobenzaldehyde (5). A 0.4 M solution of o-nitrobenzaldehyde (5) in THF was injected through capillaries by means of a syringe towards the NMR microfluidic chip with an active volume of 25 nL, and irradiated by a laser diode at 405 nm on stopped-flow. The 1H NMR acquisition parameters were as follows: 90 pulse of 8 µs, 300 accumulated scans, 0.39 s acquisition time and 0.2 s delay time, resulting in an NMR experiment time of 3 min. A 1M solution of o-nitrobenzaldehyde (5) was also tested. The only difference in the 1H NMR acquisition parameters was the number of scans (ns=500) that were averaged.

Figure 2. Circuit to bias a laser diode. The PCB consist of a heat sink, amplifiers L165 and TL082, decoupling capacitors, a potentiometer and a bipolar transistor npn. The collimation tube contained the laser diode (Figure S3) and is mounted on a Teflon holder to enable the alignment between the laser diode and the optical fiber.

RESULTS AND DISCUSSION


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The development of the photo-in situ-NMR setup aims for the irradiation of small sample volumes contained within a 3D microfluidic channel where an rf-microcoil detector is integrated, with the goal of monitoring real time photochemical transformations. As reported,2 the match between the light source dimensions and the photoreactor is important, therefore, using a nanoliter NMR coil only a miniaturized light source would have to be placed inside the NMR superconductive magnet. Nevertheless, it is difficult to fulfill these requirements and to find the electrical components to polarize the LEDs, e. g. non-magnetic resistors, are rarely available. Instead, the photo-in situ-nL-NMR setup deals with the use of an optical fiber to guide the light from the light source which is placed outside the NMR magnet towards the rf-microcoil. Therefore, two different parts comprise the photo-in situ-nL-NMR setup: the light source (A) and the NMR microfluidic chip (C) (Figure 1). Light Emitted Diodes (LEDs) and a laser diode have been the light sources of choice. LEDs provide low-energy input, long lifetime, they are inexpensive and available in a wide range of wavelengths in the emission spectrum. Lately, LEDs have found many applications in photochemical reactions. 18, 2, 29. Laser diodes produce a more monochromatic and higher power light with lower light dispersion than LEDs (Figure S4), however laser diode are more expensive and shows a lower range of wavelengths compared to LEDs. The PCB of LEDs (5 mm, “TopBright88”) and the concave mirror were placed inside an aluminum box that incorporates a fan to dissipate the excess of heating out of the LEDs (Figure S1, right). This built “in-house” system formed just by the LEDs and the mirror (excluding the optical fiber) resulted to be a very effective light source for the [2+2] photocycloaddition of (Z)-2-aryl-4-aryliden-5(4H)-oxazolones reaching complete reaction conversions within residence times up to 30 min, when a capillary coil that supports the sample was placed on top of the LEDs, in contrast to the conventional methodology that required several days.30 As mentioned above, laser diodes provide higher power than LEDs and lower dispersion (Figure S4) that contribute positively in the transmission of light through the core of the optical fiber. The laser diode maximizes the system performance when the distance between the laser diode and the optical fiber ensures that the whole beam fits into the optical fiber core diameter. Moreover, unlike the LEDs system, the laser diode driver allows to set the optical output constant during the whole experiment due to an integrated photodiode component in the circuit (Figure S2). This driver feeds back a residual portion of the laser diode keeping the radiation constant at a certain level defined by a potentiometer. As previously reported, the sensitivity of the NMR chip, expressed as mass (molar) sensitivity, Sm, resulted in 3,240 SNR • µmol -1 s -1/2 for a sample of 25 nL of H2O.28 In the current setup the linewidths was 2.5 Hz for a H2O peak, which was sufficient for the experiments performed. Figure S5 shows a 1H-NMR spectra for an ethanol sample to illustrate the resolution of our setup. Photocatalytic reductive dehalogenation of αbromoacetophenone: Model reaction for LEDs as light source.

and diethyl-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate (3) (0.55 M) in DMF (Scheme 1) was irradiated at 525 nm, the collection of NMR spectra within time (Figure 3) showed the disappearance of α-bromoacetophenone (1) and the appearance of acetophenone (2) due to dehalogenation, yielding to complete conversion, when monitoring the peak at 4.8 ppm, after 8 min of irradiation. Figure S6 shows the graphical representation of the variation of αbromoacetophenone (1) within time. Plotting ln (C1) versus time resulted in a straight line, from which a reaction rate constant k= 0.187 min-1 can be extracted. Scheme 1. Dehalogenation of α-bromoacetophenone 1. O

EtO2 C

CO2 EtEtO2 C

CO2 Et O

N 3 H

Ph 1

Br

Eosin Y DIPEA

N

525 nm DMF

4 Ph 2

Figure 3. Expansion of a collection of NMR spectra during the irradiation of a solution of α-bromoacetophenone (1) at 525 nm. Every NMR spectrum corresponds to 54 s of reaction time. The disappearance of α-bromoacetophenone 1 (4.93 ppm, CH2-Br), and the formation of acetophenone 2 (2.57 ppm, -CH3) is visible (Scheme 1). Peaks at 4.04 ppm (-OCH2) and 3.17 ppm (-CH2) correspond to diethyl-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate 3, and peak at 4.32 ppm (-OCH2) corresponds to its oxidized form 4. The peak at 3.27 ppm could be presumably attributed to the protonated DIPEA. Eosin is added in catalytic amounts and is not observed in the spectrum. Noteworthy, we are monitoring a chemical reaction looking at very small amount of material (reactant 1), from 10 nmol to 1 nmol, just to put the seemingly low signal to noise ratio of the spectra in perspective.

Intramolecular reaction of o-nitrobenzaldehyde (5): Model reaction for laser diode as light source. As the setup is modular with the light source positioned outside the magnet, it is straightforward to replace the LED source, either with LEDs of other wavelength, or with a completely different device. For example you can also replace LEDs by a laser diode as the light source for the photo-in situNMR setup. Scheme 2. Reaction of o-nitrobenzaldehyde (5).

When a degassed solution of α-bromoacetophenone (1) (0.5 M), diisopropylethylamine (DIPEA) (1 M), Eosin (0.01 M)



CHO

COOH NO2

5

NO

THF 405 nm

6

The customized circuit that polarizes the DL5146-101S laser diode allows to vary the light intensity out of the optical fiber up to 35 mW. The irradiation of a 0.4 M solution of onitrobenzaldehyde (5) (scheme 2) at a light intensity of 35 mW (figure 4), resulted in a conversion for 5 of 75% within 18 min of irradiation when the signal of –CHO is integrated (10.2 ppm). As reported by Willett et al.,31 the photoconversion of onitrobenzaldehyde (5) to nitrosobenzoic acid (6) can follow a pseudo-zero order reaction under certain experimental conditions (i.e. highly concentrated solutions). Our data in fact also fit to a second order polynomial (figure 4, right) and a reaction rate constant, k = 0.046 mol L-1 min-1, can be extracted from the initial slope of the curve following the reported approach. An error of about 10% in the k value can be estimated based on the integration of the relatively poor quality of the NMR spectra. It should be recalled that the spectral quality is not that bad considering the fact that only minute amounts of material is observed. As onitrobenzaldehyde is commonly used as a chemical actinometry,31 the value extracted for k can be used to calculate the light intensity over 405 nm in units of watts per square meter (W m-2) or light flux (F0) in our detection area. Hence, following the reported approach (see supporting info), the light flux, F0 equals 0.23 kW m-2. We also explored the system irradiating an optically dense solution of 1 M o-nitrobenzaldehyde (5) in THF. Three different light intensities were tested, 3 mW, 10 mW and 35 mW. Figure S7 shows the o-nitrobenzaldehyde concentration as a function of irradiation time at the different optical powers, indicating that the optical power has a direct effect on the reaction rate. At maximum power, the starting material was completely converted to o-nitrosobenzoic acid (6) within 40 min (Figure S7), showing the high efficiency of the setup as a very concentrated solution of reactant can be completely consumed.

Figure 4. Left: Collection of NMR spectra during the irradiation of a 0.4 M solution of o-nitrobenzaldehyde (5) in THF at 405 nm with an optical output power of 35 mW. Every NMR spectrum corresponds to 3 minutes of reaction time. Right: Graphic representation of the concentration of o-nitrobenzaldehyde (5) versus time for a 0.4 M solution.

Some aspects have to be considered in designing the system, for instance the possible heating of the sample once illuminating the microfluidic channel that may affect the

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conversion. The temperature-sensitive NMR signals of a sample of methanol were measured when irradiating with the maximum light intensity for 20 min. No chemical shift variation was observed (Figure S8), indicating that there is no effect of sample heating when using the laser diode DL5146101S in our experimental conditions (Figure 2). Another aspect in our confined system regards the selfdiffusion of molecules due to the generation of concentration gradients. Preliminary tests with sub-mm sized fibers in fact revealed diffusion due to concentration gradients to affect the measurements. We therefore opted for the light spot coming out of the optical fiber to be much wider (5 mm) than the active volume of the coil as mentioned above. To corroborate this, we carried out an NMR experiment that consisted of switching consecutively on and off the laser diode and repeating three on-off cycles consecutively (Figure S9). When light was on, a decrease in the NMR peaks of onitrobenzaldehyde (5) was observed, whilst the NMR signal remained constant in time while light was off (table S1). These results showed there is no apparent diffusion of reactants observed within our monitoring time. Obviously, such a relatively large illumination cone, reduces the effective light transfer from the laser diodes to the sample volume. The optical fiber placed at 3 mm from the sample channel defines a light cone of approximately 1 cm. The light intensity over that area considering the 35 mW that comes out of the fiber optic corresponds to 0,45 kW m-2. This approximate number corroborates well with the above calculated actinometry values.

CONCLUSIONS We report a novel set-up for in situ NMR monitoring of photochemical reactions, exploiting the benefits of small volume NMR chips. We have proved the efficiency and feasibility of the in situ monitoring of UV-vis assisted reactions for a dehalogenation of α-bromoacetophenone induced by visible light of 525 nm, and for the intramolecular reaction of o-nitrobenzaldehyde assisted at higher energy (405 nm). This setup overcomes the inefficiency of conventional setups that deals with higher volumes and therefore suffers from the limited light penetration through the reaction medium as explained by the Beer-Lambert law.32 The small volume located underneath the microcoil is in the nanoliter range and can be efficiently and uniformly irradiated by different low power light sources. It is a non-invasive method, in the sense that the fiber optic is not inserted into the sample, that presents light penetration even for highly concentrated solutions with high photon flux due to the high surface to volume ratio of microreactors.2 The potential applications of this setup go beyond monitoring of photochemical reactions and work is underway to broaden the scope of the set-up with e.g., hyperpolarization.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Experimental details and characterization of the LEDs and LD setups; Kinetic analysis for the two model reactions; Relation between light intensity and variation of concentration of reactant versus time; Stacked 1H-NMR spectra of an irradiated methanol


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sample; Percentage of o-nitrobenzaldehyde after on-off cycles (PDF).

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]. * E-mail: [email protected]

Author Contributions M. V. G. initiated and supervised the project, designed the LD system, performed experiments, discussed the data and wrote the paper. A. J. designed the LED system, performed experiments and analyzed data. F.J-M. designed and fabricated the LED and LD systems. A. d. l. H. facilitated the installation of the NMR instrument, supervised the project and discussed the data. A. H. V. optimized the NMR system, discussed the data and wrote the paper.

ACKNOWLEDGMENT We acknowledge financial support from the Spanish Ministry of Science and Innovation (CTQ2014-54987-P). M.V. G. thanks MINECO for participation in the Ramon y Cajal program and Marie Curie Reintegration Grants.

REFERENCES (1) Bach, T.; Hehn, J. P. Angew. Chem. Int. Edit. 2011, 50, 1000-1045. (2) Cambie, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noel, T. Chem. Rev. 2016, 116, 10276-10341. (3) Neumann, M.; Zeitler, K. Org. Lett. 2012, 14, 26582661. (4) Oelgemöller, M.; Shvydkiv, O. Molecules. 2011, 16, 7522-7550. (5) Coyle, E. E.; Oelgemöller, M. Photochem. Photobiol. ogical Sci. 2008, 7, 1313-1322. (6) Kind, J.; Kaltschnee, L.; Leyendecker, M.; Thiele, C. M. Chem. Commun. 2016, 52, 12506-12509. (7) Tait, K. M.; Parkinson, J. A.; Bates, S. P.; Ebenezer, W.J.; Jones, A. C. J. Photochem. Photobiol. A-Chem. 2003, 154, 179-188. (8) Lin, S.; Ischay, M. A.; Fry, C. G.; Yoon, T. P. J. Am. Chem. Soc. 2011, 133, 19350-19353. (9) He, Z.; Bae, M.; Wu, J.; Jamison, T. F. Ang. Chem.-Int. Ed. 2014, 53, 14451-14455. (10) Stoll, R. S.; Peters, M. V.; Kuhn, A.; Heiles, S.; Goddard, R.; Buhl, M.; Thiele, C. M.; Hecht, S. J. Am. Chem. Soc. 2009, 131, 357-367. (11) Mok, K. H.; Kuhn, L. T.; Goez, M.; Day, I. J.; Lin, J. C.; Andersen, N. H.; Hore, P. J. Nature 2007, 447, 106109.

(12) Goez, M. In Ann. Rep. NMR Spectro., Vol 66, Webb, G. A., Ed., 2009, pp 77-147. (13) Hore, P. J.; Broadhurst, R. W. Prog. Nucl. Mag. Res. Sp. 1993, 25, 345-402. (14) Scheffler, J. E.; Cottrell, C. E.; Berliner, L. J. J. Magn. Reson. 1985, 63, 199-201. (15) Kuhn, T.; Schwalbe, H. J. Am. Chem. Soc. 2000, 122, 6169-6174. (16) Mok, K. H.; Nagashima, T.; Day, I. J.; Jones, J. A.; Jones, C. J. V.; Dobson, C. M.; Hore, P. J. J. Am. Chem. Soc. 2003, 125, 12484-12492. (17) Kuprov, I.; Hore, P. J. J. Magn. Reson. 2004, 171, 171-175. (18) Feldmeier, C.; Bartling, H.; Riedle, E.; Gschwind, R. M. J. Magn. Reson. 2013, 232, 39-44. (19) Feldmeier, C.; Bartling, H.; Magerl, K.; Gschwind, R. M. Ang. Chem.-Int. Ed. 2015, 54, 1347-1351. (20) Anders, J.; Chiaramonte, G.; SanGiorgio, P.; Boero, G.; J. Magn. Reson. 2009, 201, 239-249. (21) Dongwan, H.; Paulsen, J.; Sun, N.; Song, Y-Q; Ham, D.; PNAS, 2014, 111, 11955-11960. (22) Boero, G.; de Raad Iseli, C.; Besse, PA.; Popovic, RS.; Sensor Actuat A-Phys. 1998, 67, 18-23. (23) Gomez, M. V.; Reinhoudt, D. N.; Velders, A. H. Small 2008, 4, 1293-1295. (24) Fratila, R. M.; Velders, A. H. Annu. Rev. Anal. Chem., Vol 4 2011, 4, 227-249. (25) Victoria Gomez, M.; Rodriguez, A. M.; de la Hoz, A.; Jimenez-Marquez, F.; Fratila, R. M.; Barneveld, P. A.; Velders, A. H. Anal. Chem. 2015, 87, 10547-10555. (26) Gomez, M. V.; Verputten, H. H. J.; Diaz-Ortiz, A.; Moreno, A.; de la Hoz, A.; Velders, A. H. Chem. Commun. 2010, 46, 4514-4516. (27) Laimgruber, S.; Schreier, W. J.; Schrader, T.; Koller, F.; Zinth, W.; Gilch, P. Angew. Chem. Int. Edit. 2005, 44, 7901-7904. (28) Fratila, R. M.; Gomez, M. V.; Sykora, S.; Velders, A. H. Nat. Commun. 2014, 5. (29) Black, K.; Singh, J.; Mehta, D.; Sung, S.; Sutcliffe, C. J.; Chalker, P. R. Sci. Rep.-UK 2016, 6, 7. (30) Serrano, E.; Juan, A.; Garcia-Montero, A.; Soler, T.; Jimenez-Marquez, F.; Cativiela, C.; Gomez, M. V.; Urriolabeitia, E. P. Chem. A. Eur. J. 2016, 22, 144-152. (31) Willett, K.; Hites, R. A. J. Chem. Ed. 2000, 77, 900902 (32 ) Shvydkiv, O.; Gallagher, S.; Nolan, K.; Oelgemoeller, M. Org. Lett. 2010, 12, 5170-5173.



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Figure 1. Schematic of the setup formed by an external light source (A), an optical fiber (B) and a reaction-detection zone (C). It comprises the illumination of a confined volume underneath the microcoil, but also the neighboring microchannel area, preventing concentration gradients to affect the measurements. The distance between the core of the optical fiber and the sample channel is 3 mm. The system is non-invasive with the optical fiber illuminating from outside and irradiating the transparent back side of the NMR chip



Figure 2. Circuit to bias a laser diode. The PCB consist of a heat sink, amplifiers L165 and TL082, decoupling capacitors, a potentiometer and a bipolar transistor npn. The collimation tube contained the laser diode (Figure S3) and is mounted on a Teflon holder to enable the alignment between the laser diode and the optical fiber.


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Illumination of nanoliter-NMR spectroscopy chips for real-time

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