ATR-FTIR Spectroscopy

Attenuated total reflectance (ATR) is a sampling methodology that enables the direct examination of solid or liquid samples without further preparation. It utilizes total internal reflection to generate an evanescent wave that penetrates the sample, providing valuable molecular information.

ATR is often used with Fourier transform infrared (FTIR) spectroscopy (ATR-FTIR spectroscopy) as it enables solids and liquid samples to be analyzed neatly – simplifying the measurement of virtually all substances.

In contrast with transmission (the other widely used sampling method), the measurement path length is independent of the thickness of the sample. ATR is an internal reflection-based method, and the sample path length is dependent on the depth of penetration of the infrared energy into the sample. A solid sample can be 100 microns thick or 100 mm thick and the recorded infrared spectrum will basically look the same. If a fluid or slurry sample is in contact with the ATR surface, the infrared spectrum of the liquid portion is recorded. It is this latter phenomenon that makes attenuated total reflectance so powerful for chemical reaction monitoring.

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ATR-FTIR spectroscopy is utilized for tasks such as identifying chemical compounds, studying molecular structures, examining surface properties, analyzing polymers, investigating biomolecules, monitoring chemical reactions, and assessing the composition of materials in industries such as pharmaceuticals, materials science, forensics, and environmental analysis.

Because ATR-FTIR can measure spectra without the need for any sample preparations or dilution, ATR spectroscopy has found applicability in analyzing solid and liquid materials. One of the earliest uses of ATR was to obtain the infrared spectra of polymer samples and films. Approximately 25 years ago, the DiComp diamond ATR was invented, which expanded the use of ATR to many new applications including chemical reaction monitoring.

In ATR-FTIR, light energy is passed through an optical material (i.e., the ATR sensor) that has two major characteristics:

1. It must be optically transparent to the frequency of the energy so that the sensor material absorbs little or none of the radiation;
   
2. The ATR sensor material has an index of refraction that is higher than that of the surrounding media so the ATR acts as a waveguide, internally reflecting the light energy.

By selecting specific optical materials and controlling the fabrication of the sensor, the number of reflections or nodes in an ATR sensor can be precisely adjusted. The effective path length of the sensor is determined by multiplying the number of internal reflections by the depth of penetration of the evanescent wave. At each node, a stationary wave of energy is emitted from the surface, contributing to the overall ATR phenomenon.

This energy is evanescent since it diminishes in intensity as a function of the distance from the surface of the sensor. Any substance in direct contact with the sensor is thus interrogated by the energy.

The depth of penetration is also dependent on the specific wavelength of energy, so when scanning a sample with modulated radiation to obtain a spectrum, the position of the peaks will be similar to that of a transmission/absorbance spectrum, however, the intensity of the individual bands will vary from the transmission/absorbance spectrum. 

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ATR-FTIR Spectroscopy: Ideal for Neat or Optically Dense Substances
Attenuated Total Reflectance (ATR) employs an optical sensor material that has a sufficiently high index of refraction to enable internal reflection within the sensor. Depending on the optical material selected and how the sensor is fabricated, the number of reflections or nodes can be carefully controlled and effective pathlengths are achieved that are well matched to optically dense samples. Any substance in direct contact with the sensor is interrogated by the energy. The intensity of the FTIR spectrum is fundamentally dependent on the number of reflections, the depth of penetration of the evanescent wave into the sample, the number of molecules of interest in the sample, and their respective absorptivity.

In contrast to the transmission technique where light must transverse the sample, in ATR-FTIR the sample thickness is not relevant. A liquid or solid sample can be 10 microns thick or 10 cm thick and in either case, a useful FTIR spectrum can be acquired. This makes ATR ideal for studying a broad range of chemical reactions since no sample preparation or dilution is required to obtain useful spectra. In addition, ATR sensors are available that are resistant to abrasion and can withstand the harsh reaction conditions associated with many chemistries.

In Contrast: Transmission IR Spectroscopy Typically Requires Sample Preparation to Obtain Useful Spectrum
To obtain a transmission spectrum of a liquid, the sample is enclosed in a cell that has infrared transparent windows and the energy must transverse the sample. The intensity of the spectrum is related to the path length of the cell and the solution being analyzed. If the sample path length is too long and/or the sample contains solvent or solute molecules that are highly infrared absorbing or highly scattering, little or no energy will reach the infrared detector. This makes the analysis of most chemical reactions difficult or impossible to perform in transmission mode. In the cases where the right path length is matched to the analyte, the transmission spectrum is acquired. Because long path length cells can be constructed, transmission IR spectroscopy can be useful to identify and track low-concentration organometallic species in homogeneous catalysis reactions. For acquiring the IR spectrum of most solids, it is necessary to dilute the sample by either mulling in nujol oil, pressing a potassium bromide pellet, or preparing an ultra-thin slice of material. 

In-situ ATR-FTIR offers numerous advantages over alternative analytical methods, including other molecular spectroscopy techniques. Researchers and scientists improve chemical development by leveraging these advantages, including:

• The mid-IR energy region yields detailed “fingerprint” spectra of starting materials, intermediates, products, and by-products allowing continual tracking of these key species as a function of time
• Real-time measurement, performed every minute or less
• In situ, no extractive sampling is required; measure chemistry without disturbing the reaction
• Non-destructive; preserving the integrity of the chemical reaction
• Measures reactions in batch, semi-batch, or continuous flow operation
• Measures reactions run under pressure or at elevated or low temperature
• Measures reactions in aqueous or non-aqueous media and over a broad range of pH
• The immersed ATR sensor is typically not affected by corrosive reagents
• Reactions with corrosive, toxic, or hazardous conditions can be monitored without sampling
• Measures solution phase; bubbles or solid particles do not interfere
• Spectral data can be converted into real-time concentration data, enabling the development of key kinetic parameters and precise endpoint determination
• A well-proven PAT method, in-situ FTIR spectroscopy supports Quality by Design (QbD) efforts and ensures that CPPs are defined and monitored
• Provides a primary means of obtaining important kinetic data and factual evidence supporting proposed mechanisms
• In-situ FTIR helps to identify and track transient intermediates that might affect product yield and quality and is key to mechanistic understanding
• Reaction trends are followed in real time, allowing for the monitoring key reaction events such as initiation, steady-state, endpoint, and decomposition

The ATR methodology is an ideal complement to FTIR Spectroscopy for in-situ, real time analysis and monitoring of chemical reactions. Reaction mixtures are typically optically dense to mid-infrared radiation. The restricted depth of penetration of infrared energy into the reaction solution that is in contact with the ATR sensor allows high-quality FTIR spectra to be recorded.

An ATR sensor fabricated of appropriate material, which is mounted at the end of a tubular probe or as part of a flow cell, enables reactions to be analyzed whether in batch or continuous flow mode, respectively. Suitable ATR sensors for analyzing chemical reactions must have the requisite index of refraction to enable internal reflection but also must perform in harsh chemical environments without degrading. Both diamond and silicon are excellent sensor materials for ATR-FTIR analysis of chemistry and the choice of which to use is dependent on the type of chemistry and the infrared peak positions that need to be tracked.

When ATR-FTIR spectroscopy is employed the following benefits are achieved:

• Reactions are monitored in real time, in-situ under actual reaction conditions
• Information about reaction trends, progress, and kinetics are readily acquired
• Key transient reaction intermediates are observed aiding in mechanism studies
• Exposure to toxic chemicals or hazardous, energetic reactions is minimized
• An understanding of the relationship between reaction variables and overall reaction performance is greatly enhanced

Because of the speed of acquiring spectra by FTIR and the development of a new generation of chemical resistant ATR sensors, the use of this combined technology revolutionizes the means to acquire chemical kinetics and mechanistic information.

The ReactIR 702L is the first FTIR spectrometer that truly merges the power of real-time, in-situ FTIR with equivalent operational convenience. ReactIR is ready for every chemist and for every experiment.

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Probe- and flow-based sampling technologies, allowing scientists to investigate both liquid and gas phase chemistry in batch or continuous setups. 

Common Attenuated Total Reflectance (ATR) spectroscopy application areas include:

1. Nguyen, T., Shamsabadi, A. A., & Bavarian, M. (2023). Coupling ATR-FTIR spectroscopy with multivariate analysis for polymers manufacturing and control of polymers’ molecular weight. Digital Chemical Engineering, 7, 100089. https://doi.org/10.1016/j.dche.2023.100089
2. Simone, E., Beveridge, G., Sillers, P., Webb, J., George, N., & Hone, J. (2022). Analysis of the Dissolution and Crystallization of Partly Immiscible Ternary Mixtures Using a Composite Sensor Array of In Situ ATR-FTIR, Laser Backscattering, and Imaging. Industrial & Engineering Chemistry Research, 61(50), 18514–18529. https://doi.org/10.1021/acs.iecr.2c03494
3. Li, Z., & Zhang, B. (2022). Investigation of Glycine Polymorphic Transformation by In Situ ATR-FTIR and FT-Raman Spectroscopy. Crystals, 12(8), 1141. https://doi.org/10.3390/cryst12081141
4. Lomont, J. P., Ralbovsky, N. M., Guza, C., Saha-Shah, A., Burzynski, J., Konietzko, J., Wang, S., McHugh, P. C., Mangion, I., & Smith, J. A. (2022b). Process monitoring of polysaccharide deketalization for vaccine bioconjugation development using in situ analytical methodology. Journal of Pharmaceutical and Biomedical Analysis, 209, 114533. https://doi.org/10.1016/j.jpba.2021.114533
5. Zapata, F., López-Fernández, A., Ortega-Ojeda, F., Quintanilla, G., García-Ruiz, C., & Montalvo, G. (2021). Introducing ATR-FTIR Spectroscopy through Analysis of Acetaminophen Drugs: Practical Lessons for Interdisciplinary and Progressive Learning for Undergraduate Students. Journal of Chemical Education, 98(8), 2675–2686. https://doi.org/10.1021/acs.jchemed.0c01231
6. Wang, Z., Gérardy, R., Gauron, G., Damblon, C., & Monbaliu, J. (2019). Solvent-free organocatalytic preparation of cyclic organic carbonates under scalable continuous flow conditions. Reaction Chemistry and Engineering, 4(1), 17–26. https://doi.org/10.1039/c8re00209f
7. Dunn, A. L., Leitch, D. C., Journet, M., Martin, M. C., Tabet, E., Curtis, N. F., Williams, G. D., Goss, C. W., Shaw, T., O’Hare, B., Wade, C. E., Toczko, M. A., & Liu, P. (2019). Selective Continuous Flow Iodination Guided by Direct Spectroscopic Observation of Equilibrating Aryl Lithium Regioisomers. Organometallics, 38(1), 129–137. https://doi.org/10.1021/acs.organomet.8b00538
8. Clagg, K., Hold, S., Kumar, A., Koenig, S. G., & Angelaud, R. (2019). A telescoped Knochel-Hauser/Kumada-Corriu coupling strategy to functionalized aromatic heterocycles. Tetrahedron Letters, 60(1), 5–7. https://doi.org/10.1016/j.tetlet.2018.11.014
9. Folsom, T. M., & Darensbourg, D. J. (2019). Kinetic studies of thermal dissociation of carbon monoxide ligands from manganese tri- and tetra-carbonyl derivatives containing the bulky dipiperidylmethane ligand, CH2Pip2. Inorganica Chimica Acta, 484, 443–449. https://doi.org/10.1016/j.ica.2018.09.004
10. Hammarback, L. A., Robinson, A., Lynam, J. M., & Fairlamb, I. J. S. (2019). Mechanistic Insight into Catalytic Redox-Neutral C–H Bond Activation Involving Manganese(I) Carbonyls: Catalyst Activation, Turnover, and Deactivation Pathways Reveal an Intricate Network of Steps. Journal of the American Chemical Society, 141(6), 2316–2328. https://doi.org/10.1021/jacs.8b09095
11. McMillan, A., Steven, A., Ashworth, I. W., Mullen, A. B., Chan, L. W., Espinosa, M. P., Pilling, M. J., Raw, S. A., & Jones, M. (2019). Stereoretentive Etherification of an α-Aryl-β-amino Alcohol Using a Selective Aziridinium Ring Opening for the Synthesis of AZD7594. Journal of Organic Chemistry, 84(8), 4629–4638. https://doi.org/10.1021/acs.joc.8b01062
12. Sagmeister, P., Williams, J. D., Hone, C. A., & Kappe, C. O. (2019). Laboratory of the future: a modular flow platform with multiple integrated PAT tools for multistep reactions. Reaction Chemistry and Engineering, 4(9), 1571–1578. https://doi.org/10.1039/c9re00087a
13. Rao, K. S., St-Jean, F., & Kumar, A. (2019). Quantitation of a Ketone Enolization and a Vinyl Sulfonate Stereoisomer Formation Using Inline IR Spectroscopy and Modeling. Organic Process Research & Development, 23(5), 945–951. https://doi.org/10.1021/acs.oprd.9b00042
14. Dreimann, J. M., Kohls, E., Warmeling, H., Stein, M., Guo, L., Garland, M., Dinh, T., & Vorholt, A. J. (2019). In Situ Infrared Spectroscopy as a Tool for Monitoring Molecular Catalyst for Hydroformylation in Continuous Processes. ACS Catalysis, 9(5), 4308–4319. https://doi.org/10.1021/acscatal.8b05066
15. Violet, L., Mifleur, A., Vanoye, L., Nguyen, D. K., Favre-Réguillon, A., Philippe, R., Gauvin, R. M., & Fongarland, P. (2019). Online monitoring by infrared spectroscopy using multivariate analysis – background theory and application to catalytic dehydrogenative coupling of butanol to butyl butyrate. Reaction Chemistry and Engineering, 4(5), 909–918. https://doi.org/10.1039/c8re00238j
16. Herman, C., Haut, B., Halloin, V., Vermylen, V., & Leyssens, T. (2012). Use of in situ Raman, FBRM® and ATR-FTIR Probes for the Understanding of the Solvent-Mediated Polymorphic Transformation of II-I Etiracetam in Methanol. Crystal Growth & Design, 16, 49–56. https://difusion.ulb.ac.be/vufind/Record/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/69679/Details
17. Makosch, M., Kartusch, C., Sá, J., Duarte, R. M., Van Bokhoven, J. A., Kvashnina, K. O., Glatzel, P., Fernandes, D. J., Nachtegaal, M., Kleymenov, E., Szlachetko, J., Neuhold, B., & Hungerbühler, K. (2012). HERFD XAS/ATR-FTIR batch reactor cell. Physical Chemistry Chemical Physics, 14(7), 2164–2170. https://doi.org/10.1039/c1cp21933b
18. Salehpour, S., & Dubé, M. A. (2011). Reaction Monitoring of Glycerol Step-Growth Polymerization Using ATR-FTIR Spectroscopy. Macromolecular Reaction Engineering, 6(2–3), 85–92. https://doi.org/10.1002/mren.201100071
19. And, B. O., & Glennon, B. (2005). Application of in Situ FBRM and ATR-FTIR to the Monitoring of the Polymorphic Transformation of d-Mannitol. Organic Process Research & Development, 9(6), 884–889. https://doi.org/10.1021/op0500887
20. Liotta, V., & Sabesan, V. (2004). Monitoring and Feedback Control of Supersaturation Using ATR-FTIR to Produce an Active Pharmaceutical Ingredient of a Desired Crystal Size. Organic Process Research & Development, 8(3), 488–494. https://doi.org/10.1021/op049959n