NMR Spectroscopy in Microfluidic Stripline NMR Chips

Microfluidic stripline NMR technology not only allows for NMR experiments to be performed on small sample volumes in the submicroliter range, but also experiments can easily be performed in continuous flow because of the stripline’s favorable geometry. In this study we demonstrate the possibility of dual-channel operation of a microfluidic stripline NMR setup showing oneand twodimensional H, C and heteronuclear NMR experiments under continuous flow. We performed experiments on ethyl crotonate and menthol, using three different types of NMR chips aiming for straightforward microfluidic connectivity. The detection volumes are approximately 150 and 250 nL, while flow rates ranging from 0.5 μL/min to 15 μL/min have been employed. We show that in continuous flow the pulse delay is determined by the replenishment time of the detector volume, if the sample trajectory in the magnet toward NMR detector is long enough to polarize the spin systems. This can considerably speed up quantitative measurement of samples needing signal averaging. So it can be beneficial to perform continuous flow measurements in this setup for analysis of, e.g., reactive, unstable, or mass-limited compounds. N magnetic resonance (NMR) spectroscopy is a powerful technique and an important tool for complex molecular structure determination and mixture analysis in biology and chemistry. However, because of the inherent low sensitivity of the technique, relatively large amounts of sample are needed in order to prevent very long signal averaging for obtaining meaningful spectra. Since the signal-to-noise ratio (SNR) of the measurement scales linearly with the number of spins contributing to the signal but scales only with square root of the number of scans, for mass limited samples it can become a problem to achieve sufficient SNR in the time available. Moreover, if the sample volume does not match the coil volume (typically 500 μL for commercial NMR probes), substantial dilution of the sample is needed, and as a consequence the signal of the sample may be obscured by the signal of the solvent. Furthermore, the composition of the sample itself should be constant during the acquisition in order to measure a representative spectrum. In some cases, e.g., for fast reactions and/or long measurements, such as 2D or C experiments on unstable compounds, changes in composition of the sample during the total measurement time result in spectra that reflect only an approximation of the average composition of the sample. A possible solution to these problems is miniaturization, as reducing the diameter of the NMR coil increases the sensitivity per amount of spins. Therefore, since the introduction of the first solenoidal microcoils and the first planar microcoils, microcoils are an extensively explored topic in NMR research. In the past decade, several approaches to microscale NMR include solenoid coils, planar coils, Helmholtz coils, and striplines/microslots. Microcoils are not only more suited for measuring masslimited samples, but depending on the design, also in situ measurements in a microfluidic setup are facilitated. In this contribution we investigate the use of stripline NMR microcoils coupled to a standard microfluidic setup for continuous flow NMR. Microfluidic continuous flow NMR can be of importance in chemistry, where in-line analysis can be advantageous especially in applications where samples are unstable or in quantitative high-throughput analysis. Another approach in microfluidic NMR is remote detection NMR, where separation of encoding and detection steps results in a higher sensitivity. Some applications of microfluidic NMR focus on in situ monitoring of reaction kinetics (including 2D structural analysis, e.g., in synthetic chemistry, metabolic studies, drug delivery), continuous flow quality control, and fast quantitative analysis (unbiased for samples with long relaxation times). Also, microfluidic NMR enables the hyphenReceived: September 25, 2016 Accepted: January 23, 2017 Published: January 23, 2017 Article