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. 2023 Jan 31;95(6):3204–3209. doi: 10.1021/acs.analchem.2c03347

Measurement of Minute Liquid Volumes of Chiral Molecules Using In-Fiber Polarimetry

Florian Schorn †, Arabella Essert ‡, Yu Zhong §, Sahib Abdullayev §, Kathrin Castiglione ‡, Marco Haumann §,$,*, Nicolas Y Joly †,*
PMCID: PMC9933876  PMID: 36720470

Abstract

graphic file with name ac2c03347_0007.jpg

We report an optofluidic method that enables to efficiently measure the enantiomeric excess of chiral molecules at low concentrations. The approach is to monitor the optical activity induced by a Kagome-lattice hollow-core photonic crystal fiber filled with a sub-μL volume of chiral compounds. The technique also allows monitoring the enzymatic racemization of R-mandelic acid.

Introduction

R- and S-enantiomers of a chiral molecule are non-superimposable mirror images from each other. While their chemical and physical bulk properties are mostly identical,1 their biological effect often differs drastically.2 For this reason, the analysis of chiral molecules plays an important role in, e.g., food, cosmetics, and pharmaceutical industries..1,2 A well-known example here is limonene. R-limonene can be extracted from citrus fruits and has an orange smell. It is used in both food and cosmetics industries. Its counterpart, the S-enantiomer on the other hand smells like turpentine.3 In the pharmaceutical sector, active components are often applied in small doses of a few μg to a few g per day.4 As a result, the production capacity is usually much lower than for other chemical compounds. At the same time the purity of pharmaceutical products is subject to strict requirements since already small doses of impurities can have a harmful effect. This also applies to chiral molecules since the difference between two enantiomers can completely change the biological impact.2 An example is the drug thalidomide, which was prescribed to treat anxiety and insomnia. In this case, the harmful substance is the S-enantiomer of the pharmaceutically active R-thalidomide itself. While the R-enantiomer is a very reliable sleeping drug, the S-enantiomer is highly teratogenic, causing malformations in unborn children. In the case of thalidomide, these side effects cannot be completely avoided even by using a pure enantiomer because the other one can nevertheless be formed by an in vivo racemization reaction.2,5 To avoid such problems for newly developed drugs in the future, it is necessary to carefully monitor their production process.

In conventional chemical processes, both enantiomers are often produced in equal parts, as racemate. However, due to their almost identical chemical and physical properties, it is very difficult to separate the two enantiomers with purely physical methods. The existing separation methods are mainly based on different forms of chiral chromatography.6 In order not to waste the undesired enantiomer, it is also often recycled using a racemization reaction, using, for example, an acid or base catalyst or an enzyme. A variety of natural enzymes are known that can specifically interconvert enantiomers, such as amino acid racemases7 or the mandelate racemase.8 A more elegant approach, on the other hand, would be enantio-selective reactions, in which the desired enantiomer can be produced in a targeted manner. One way of doing this is to modify the steric demand of the homogeneous catalyst.9,10 Another way is the use of biological processes, such as enzymes or bacteria, which often have a very high enantioselectivity.11 Regardless of the way enantiopure molecules are produced or separated from each other, the purity must be carefully analyzed. Different enantiomers of chiral molecules are distinguished by measuring their optical activity. This consists of analyzing the rotation of a linearly polarized beam propagating through a sample by an angle α

graphic file with name ac2c03347_m001.jpg 1

where the enantiomeric excess eex describes the ratio of the R- to S-enantiomers

graphic file with name ac2c03347_m002.jpg 2

and αracem corresponds to the absolute angle measured for the racemate case when both enantiomers have equal concentrations, L is the optical path length, and c is the total concentration of the chiral component with the molar mass M. According to the convention, only the ee of the excess enantiomer is used such that ee is always positive. The specific rotation of the chiral component [α]λT depends on the temperature T and the wavelength λ. It was first introduced by Biot12 as

graphic file with name ac2c03347_m003.jpg 3

where A(T) is a fitting function of the temperature. For the Biot equation, it is assumed that the used wavelength is far from any absorption resonance. Since this is rarely the case in reality, a Drude model of the specific rotation

graphic file with name ac2c03347_m004.jpg

is usually preferred.12 It however requires careful measurement of the absorption resonance wavelength λi and its respective weight Ai. The temperature dependence on the other hand in practice is often neglectable. More important is the effect of the environment on the chiral molecule under study and in particular the influence of solvent, which can strongly affect the parameter Ai.13 Optical activity is commonly measured at a wavelength of 589 nm and at ambient temperature. By operating at shorter wavelengths, the specific rotation can be increased by a factor 2 to 5. However, this may also lead to undesired UV-induced interactions. To improve the sensitivity of the measurement, increasing the path length through the sample does not present any particular physical issue. It is however always accompanied by an increase in the required liquid volume. Analyzing pharmaceutical compounds can then become extremely expensive; the production costs for these are often more than a 100 times higher than for common bulk chemicals.11

Here, we describe the use of a hollow-core photonic crystal fiber (HC-PCF) as an optofluidic alternative to the conventional 1–10 cm wide cuvettes. An HC-PFC consists of a periodic arrangement of glass capillaries that surround the empty core region. The entire HC-PCF can serve as a container for the fluid under study while maintaining guidance of the analyzing light in its core region (Figure 1).

Figure 1.

Figure 1

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(a) Micrograph of the Kagomé-lattice HC-PCF used for the experiment. Concept of the experiment. The unit cell of the Kagomé lattice cladding is indicated in blue. The near-field of the output end of the fiber, recorded with a CCD camera, is shown on the SEM of the fiber. (b) Concept of the experiment. The molecules that fill the entire length of the HC-PCF are probed by the laser beam. Analysis includes polarization, mode profile, and spectrum.

Experimental Section

The inset of Figure 1 shows a micrograph of the Kagomé-lattice hollow-core photonic crystal fiber used for the current work.

The silica parts appear in gray. The dark regions are the channels that are filled with a fluid. While the entire fiber can be filled with liquid or gas, the light can still be guided in its core region, as long as the refractive index of the fluid is lower than that of the glass. The near-field of the output of the fiber is superimposed on the micrograph of the fiber in Figure 1. As the result, such broadband waveguides are an ideal platform for any kind of light–matter interaction and it allows many different methods of analysis.14,15 In the case of optical activity, the signal strength can easily be improved by a factor of 5 to 10 by simply increasing the fiber length while keeping the volume of the sample minute. Perfectly symmetric HC-PCF exhibits extremely high polarization purity.16,17 In our case, imperfections of the fiber itself as well as stress can cause a residual birefringence, which has to be considered. Here, we used the very same piece of fiber for all of the measurements. We can therefore easily eliminate this common contribution by subtraction of the value for the racemic mixture. Deformations caused by the pressure required for filling can also be neglected. Since the fiber is filled completely with liquid and all measurements are done with no liquid flow, the pressures of the core and of the surrounding capillaries balance each other. As first reported by Chen et al.18 in-fiber optical methods, in their case absorption spectroscopy, can also be used to analyze chemical reactions in real-time. Further examples of chemical reactions, measurement methods, and improvements in methodology were later reported by Cubillas et al.,15,19 Unterkofler et al.,20 Ponce et al.,21 and ourselves.14 In the current paper, we show how in-fiber polarimetry can allow to determine the concentration of chiral component by measuring the induced optical activity.

The experimental setup is shown in Figure 2. All experiments were carried out at room temperature. A Kagome-type HC-PCF with a core size of 23 μm was used for the experiments. The characteristic star-of-David unit cell of the Kagome-lattice fiber is indicated in blue on the micrograph of the fiber on Figure 1. The maximal fiber length that we used is 7 dm. The two ends of the fibers were clamped inside custom-made liquid cells. The dead volume of one of the liquid cells was ca. 50 μL. To fill the fiber, the liquid was first placed in a pressure vessel and then pressurized with nitrogen gas at 12 bar. At first, we flushed the residual air out of the fiber by opening the valves of both liquid cells. In a second step, the bypass valve was closed while keeping one liquid cell opened. The flow through the fiber can be stopped by opening the bypass valve to equalize the pressure on both sides. The pump consists of a 532 nm continuous wave laser diode system with an output power of 50 mW. We ensure that any residual ellipticity of the polarization prior the fiber is eliminated using a λ/4-waveplate (Figure 2). The orientation of the linearly polarized light is adjusted with a λ/2-waveplate prior the coupling lens. The laser was coupled into the fiber core using an aspheric lens (f = 25 mm). The fiber output was sent to a polarimeter (Thorlabs, PAX1000VIS/M).

Figure 2.

Figure 2

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Experimental setup. A Kagome fiber (SEM on Figure 1) is clamped with both ends into two liquid cells. The solution to be analyzed is filled into a pressure vessel and pressed into the fiber with 12 bar N2 gas. The pump is a 532 nm CW microchip laser. A set of waveplates control the input polarization at the input of the fiber. Polarization after the fiber is analyzed with a polarimeter. A CCD camera monitored the near-field of the fiber.

Results and Discussion

As a proof of principle experiment, we first measured the specific rotation of commercially available chemicals. Starting from pure 2-butanol (RS: Carl Roth, >98.5%; R: Acros organics, >99%; S: Alfa Aesar, >98%) dissolved in methanol, we filled three lengths of hollow-core PCFs with mixtures of pure 2-butanol with different enantiomeric excess. The value of the measured optical activity over the enantiomeric excess is shown in Figure 3. All measurement points were averaged over a time span of 10 s. The measured value for pure racemic was used as a reference and subtracted from all measured points to avoid any influence of the birefringence of the fiber. As expected from eq 1, we observed a clear linear dependence on the effective interaction length as well as on the concentration of the chiral compound.

Figure 3.

Figure 3

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Measured optical activity for pure 2-butanol over enantiomeric excess for different fiber lengths; points are the measured values; and lines correspond to eq 1; T = 20 °C; λ = 532 nm (continuous wave).

Using eq 1, we extracted the specific rotation αλ=532 nmT=20° for R-2-butanol of −17.1 ± 0.2° mL g–1 dm–1.

Since there are no resonances in the close vicinity of the used wavelength, we use the Biot equation to compare our measurements with the literature values. In the present case, we used chemicals for which [a]58920 is known. This is close enough to our operating wavelength (λ = 532 nm), so that we consider A(T) to be the same for both wavelengths. Our measured value is in very good agreement with the manufacturer’s value of −16.5 ± 0.25° mL g–1 dm–1 at 532 nm (−13.9 ± 0.2° mL g–1 dm–1 for 589 nm).22 In the current case, the hollow-core fiber is 6 dm offering a 6x gain in comparison to a conventional cuvette while requiring a sample volume of less than 1 μL. The total volume contrasts with the internal volume of a conventional cuvette that is between 200 μL and 20 mL. This could be further reduced through further optimization of the liquid cells and the filling mechanism as it has been described by Unterkofler et al.23 and Nissen et al.24 The path length could also be further increased through optimization of the guidance properties.

Since chiral chemicals are rarely used as highly concentrated pure substances in the pharmaceutical industry, we carried out an additional series of measurements with 2-butanol diluted in methanol. The results for both R- and S-2-butanol are shown in Figure 4. Since the absolute value of the specific rotation of the two enantiomers is expected to be identical, but with opposite signs, the absolute value of the optical activity is shown here for better comparability. For each concentration, we measured the output polarization state for five different initial orientations of the input linear polarization. The mean value of the optical activity of these five measurements is used in the plot, and the absolute standard deviation from the mean value is displayed as error bars. The highest standard deviation that we measured is 1.7°, which is more than 7 times higher than the polarimeter’s accuracy of 0.25°. We attributed this error to the presence of higher-order spatial modes propagating in the Kagome hollow-core fiber. Although these modes will all be affected in the same manner by the optical activity of the compound, their respective contribution is likely to change due to in-coupling perturbation, resulting in a random modification of the output polarization.25 Between each measurement, we monitored the output mode and adjusted the in-coupling so as to limit the contribution from higher-order modes as much as possible. As a consequence, the estimation of the concentration error is still about 1 order of magnitude larger than for a conventional device e.g., Anton Paar, MPC150. However, our method has a lot of room for improvement. The Kagomé fiber that we used has losses of about 1dB/m and must be kept straight. By contrast, the state-of-the-art single-ring fiber, which also guides light by antiresonance, can have losses below 5 dB km–1 in the visible region and offer exceptional polarization purity.16,17 Additionally, a single-ring HC-PCF can be made endlessly single mode so as to prevent the propagation of higher-order modes.26 Using a longer length of a single-mode single-ring fiber would significantly improve the accuracy of the method.

Figure 4.

Figure 4

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Absolute value for the measured optical activity for R- and S-2-butanol dissolved in methanol over enantiomeric excess; the ee of the component in excess was used; points are the measured values; and lines correspond to eq 1; c2-But, tot = 0.044 g mL–1, L = 70 cm; T = 20 °C; λ = 532 nm (continuous wave).

From the data presented in Figure 4, we calculated a specific rotation [α]532T for R-2-Butanol of −16.5 ± 3.2° mL g–1 dm–1 and +17.7 ± 2.6° mL g–1 dm–1 for S-2-Butanol. As expected, the less concentrated the compound, the smaller the rotation of the linear input polarization and the larger the uncertainty. However, both values, although slightly different, are very close to the value given by the manufacturer.

We validated our method by evaluating [α]λ=532T for R-mandelic acid and R-limonene. Table 1 presents the results of our measurements. In each case, we obtained a very good agreement with the known data.

Table 1. Comparison of Measured and Expected Optical activities for Different Chiral Components: Limonene: 0.136 g mL–1; 2-Butanol: 0.074 g mL–1 in Methanol; Mandelic Acid: 0.015 g mL–1 in Water.

  [α]53220/° mL g–1 dm–1  
  measured literature
R-2-butanol –16.5 ± 3.2 –16.5 ± 0.2522a
S-2-butanol +17.7 ± 2.6 +16.5 ± 0.2522a
R-mandelic acid –173.3 ± 2.1 –190.0 ± 2.027a
R-limonene +144.3 ± 2.6 +145.1 ± 0.028b
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a

Estimated with eq 3 using the value of 589 nm reported by the manufacturer.

b

Value obtained via linear interpolation of simulated data from ref (28).

In a second step, we use our technique to monitor the evolution of the enantiomeric excess during the enzymatic racemization of R-mandelic acid (RMA). In this reaction, we use mandelate racemase from Pseudomonas putida ATCC 12633 as the catalyzing enzyme. It was produced as described by Golombek and Castiglione29 with minor modifications: For strep-tag II affinity chromatography, a binding buffer containing 10 mM MOPS, pH 8, 150 mM NaCl, 3.3 mM MgCl2, and 0.01% w/v bovine serum albumin (BSA) was used, supplemented with additional 50 mM D-biotin for elution. The purified enzyme was then desalted by PD-10 columns packed with Sephadex G-25 resin (Cytiva) and stored at −80 °C after freezing in liquid nitrogen. The storing buffer is composed of the binding buffer containing 25 mM instead of 150 mM NaCl. For the reaction experiments, 100 mL of a basic solution was mixed. It consists of 1 M MOPS buffer (Carl Roth, >99%) with a pH value of 7.5, 25 mM NaCl (Carl Roth, >99%), 3.3 mM MgCl2 (Carl Roth, >99%), and 0.005 w % BSA (Carl Roth, >98%). From this basic solution, 5 mL was used to create a diluted enzyme stock solution with an enzyme concentration of 6.4 μg mL–1. This solution was stored at 4 °C. For each experiment, 9 mL of a 0.017 g mL–1 R-mandelic acid solution was created out of the basic solution as well. The reaction was initiated by adding 1 mL of the enzyme stock solution to the mandelic acid solution, resulting in a final enzyme concentration of 0.64 μg mL–1 and a final mandelic acid concentration of 0.015 g mL–1. Since the concentration of all other components remained equal in both mixtures, the procedure ensured that the initial concentrations were always the same. We neglected the small differences in mixing volumes.

We realized the racemization reaction at room temperature. The results for the evolution of ee during the reaction are shown in Figure 5. The stated age corresponds to the time that the enzyme was stored as diluted stock solution at 4 °C before its use. As expected, the presence of enzymes yields the decay of the enantiomeric excess. It can be expected that at the end of the racemization reaction, both concentrations of the R- and S-enantiomers are equal and the optical activity due to the chiral chemicals should fall to zero. The two solutions are mixed and then immediately filled into the fiber. At the end of the procedure, the fundamental spatial mode of the fiber was adjusted by imaging the near-field at the output of the fiber. The filling of the fiber and the optimization of the propagating mode can take up to 10 min during which the reaction is already taking place. The impact of this initial deadtime used for filling the fiber and optimizing the propagating mode can be estimated using the Michaelis–Menten equation for the initial reaction rate with the turnover number kcat = 1124 s–1 and the Michaelis constant Km = 1.1 mM.30 In our case, a value of 90–80% for eeRMA is expected at the beginning of the measurement. While this is the case for one of our experiments (red curve on Figure 5), we see that the other experiment starts at a much lower enantiomeric excess of around 60%. Since the ee is directly measured through the evaluation of the rotation angle, contribution from higher-order modes may be the reason of the discrepancy with the expected value of ee (t = 10 mn). Although we optimize the in-coupling by visualizing the near-field at the output of the fiber, the modal content from one experiment to the next may vary. By contrast with the previous experiments, where ee is fully known and fixed allowing repetition of the same experiment so as to reduce experimental errors, we cannot modify the experimental conditions during the entire duration of the reaction. Another significant difference is that we worked with ∼10× less concentration of mandelic acid in order not to damage the enzymes because of the pH value. As a result of this, the sensitivity of the measurement is significantly reduced in comparison to our previous experiments. Using the standard deviation of 1.7° that we evaluated in our previous experiments, we estimated 6.4% uncertainty for the enantiomeric excess due to the lower concentration. This is compatible with the observed fluctuations (Figure 5).

Figure 5.

Figure 5

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Measured enantiomeric excess over reaction time for a R-mandelic acid/mandelate racemase solution. Enzyme concentration: 0.64 μg mL–1; mandelic acid concentration: 0.015 g mL–1; L = 100 cm; T = 20 °C; λ = 532 nm (continuous wave).

Conclusions

In summary, we showed that we can retrieve the optical activity of chiral molecules by measuring the rotation of the input linear polarization of a beam propagating in a Kagome-lattice hollow-core fiber filled with the enantiomer under study. The required volume of the chiral chemical is only 0.5 μL, which is orders of magnitude lower than for conventional methods. Although we use minute volumes, the optical path length of the measurement is significantly increased. The overall method could be improved even more using a single-ring fiber, so as to prevent higher-order modes. Additionally, our procedure allows live monitoring of the dynamical change of the ee during a racemization reaction. Such a tool could be useful to analyze and optimize the processes involved in racemization reaction. We do not doubt that this technique could also be used during the reaction aiming at purifying one specific enantiomer. This could serve efficiently for the development of new drugs in the pharmaceutical industry.

Acknowledgments

F.S. gratefully acknowledges financial support from the International Max Planck Research School for the Physics of Light in Erlangen. M.H. gratefully acknowledges financial support from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project-ID 431791331–SFB 1452 (CLINT).

Glossary

Abbreviations

HC

hollow core

ORD

optical rotary dispersion

PCF

photonic crystal fiber

RMA

R-mandelic acid

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.analchem.2c03347.

  • Optical setup and alignment procedure; verification of the fiber-input polarization; details of the liquid cells; detailed measurements for mandelic acid and limonene (related to Table 1); detailed information about enzyme production (PDF)

The authors declare no competing financial interest.

Supplementary Material

ac2c03347_si_001.pdf (170.9KB, pdf)

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Supplementary Materials

ac2c03347_si_001.pdf (170.9KB, pdf)

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