FTIR Spectroscopy

Fourier Transform Infrared (FTIR) spectroscopy is an analytical methodology used in industry and academic laboratories to understand the structure of individual molecules and the composition of molecular mixtures. FTIR spectroscopy uses modulated, mid-infrared energy to interrogate a sample. The infrared light is absorbed at specific frequencies directly related to the atom-to-atom vibrational bond energies in the molecule. When the bond energy of the vibration and the energy of mid-infrared light are equivalent, the bond can absorb that energy. Different bonds in a molecule vibrate at different energies, and therefore absorb different wavelengths of the IR radiation. The position (frequency) and intensity of these individual absorption bands contribute to the overall spectrum, creating a characteristic fingerprint of the molecule.

FTIR spectroscopy has broad use and applicability in the analysis of molecules important in the pharmaceutical, chemical and polymer industries. FTIR analysis is used in both industry and academic laboratories to better understand the molecular structure of materials as well as the kinetics, mechanism and pathways in chemical reactions and catalytic cycles. FTIR spectroscopy is used to ensure that raw materials, intermediate compounds and final products are within specification. In chemical and pharmaceutical R&D, in-situ FTIR spectroscopy is used to help scale up chemical reactions, optimize reaction yield and minimize by-product impurities. In chemical and pharmaceutical production, FTIR spectroscopy functions as a process analytical technology (PAT), ensuring that processes are stable and in control and achieve final product specifications.

 

Understanding complex chemical reactions is a major challenge and opportunity for chemists and engineers. Better fundamental insight into how chemical reactions work and the ideal conditions to develop, scale up and operate processes are the key to achieving final product yield, purity and cost objectives. The capability of in-situ FTIR to provide real-time tracking and monitoring of reaction progress is ideal for developing insight into how reactions work and the means to optimization. Reaction insight comes from identifying and profiling the variations of key reaction species including reagents, intermediates, products and by-products as the reaction proceeds. Important reaction events are revealed including initiation, steady-state condition and endpoint. Rates of reaction and other key kinetic parameters are determined from this real-time profiling information, as well as support for proposed mechanisms. With the significant amount of data points collected, in-situ FTIR is highly useful in data rich experimentation, such as Reaction Profile Kinetic Analysis (RPKA). To summarize, all of the above are readily achieved by in-situ FTIR, whereas traditional offline analyses are often impossible to perform (under pressure, highly caustic, air/moisture sensitive, toxic, etc.). Additionally, offline analyses can take several minutes to hours for a result, and/ or are susceptible to non-reproducibility.

To measure chemistry in real time requires the transfer of modulated infrared radiation into a reaction vessel or continuous flow apparatus, and then the return of the unabsorbed energy to the spectrometer. To accomplish this, ReactIR technology uses an internal reflection (Attenuated Total Reflectance/ATR) sensor mounted at the end of a tubular optical probe that can be inserted into a chemical reaction, or an ATR sensor that is an integral part of a cell monitoring continuous flow reactions.

The ATR method is an ideal complement to FTIR instrumentation for analysis and monitoring of chemical reactions. The restricted depth of penetration of the infrared energy into the sample permits high-quality FTIR spectra of optically dense reaction mixtures. The neat solution phase of a chemical reaction is measured and bubbles, particles, catalysts, biological solids, water, etc., do not interfere with the measurement.

Suitable ATR sensors for analyzing chemical reactions must have the requisite index of refraction to enable internal reflection and must also perform in harsh chemical environments without degrading. Both diamond and silicon are excellent sensor materials for FTIR-ATR, and the choice of which to use is dependent on the type of chemistry and the infrared peak positions that need to be tracked. 

In-situ FTIR spectroscopy is widely used in research, early and late development, scale up and reaction optimization. This technology analyzes batch and flow reactions, reactions in polar and non-polar solvents, and reactions over broad pH, temperature and pressure ranges. Data collection is automated, with qualitative or quantitative information typically generated every minute. In-situ FTIR spectroscopy provides the data to support Design of Experiment (DoE) Studies and other statistical analysis methods without the wait and occasional complex sampling/prep for offline analysis. This means that rather than running a large number of reactions to understand rate dependencies, just a few experiments can provide the necessary information to determine the driving forces of a reaction. In-situ FTIR yields reaction kinetics parameters and defines critical control parameters (CPP) that can be seamlessly transferred to production. With its capability to detect and identify reaction intermediates and measure kinetic parameters, in-situ FTIR is widely used to provide support for proposed reaction mechanisms. 

Common in-situ FTIR Spectroscopy applications include:

• Epoxides
• Alkylation Reactions and Friedel-Crafts Alkylation Reactions
• Polymerization Reactions
• High Pressure Reactions
• Hydrogenation Reactions
• Hydroformylation or Oxo Synthesis/Process
• Grignard Reaction Mechanisms
• Halogenations
• Lithiations
• Biocatalysis | Enzymatic Catalysis
• Flow Chemistry
• Metal and Non-Metal Catalyzed Reactions
• Suzuki and Related Cross-Coupling Reactions
• C-H Activation Reactions

In-situ FTIR-ATR 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 continually tracking of these key species as a function of time
• Real-time measurement, performed every minute or less
• In-situ, no extractive sampling 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 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

• Metal-Mediated Chemistry
• Chemo- and Biocatalysis
• C-H Activation
• Mechanistic Studies
• Reaction Kinetics/Reaction Progress Kinetics Analysis
• Catalyst Cycles
• Polymerization Kinetics

• Chemical Synthesis
• Hydrogenation Reactions
• Metal Catalyzed Reactions 
• Biocatalysis/Enzymatic Catalysis
• Crystallization and Recrystallization (Supersaturation)
• Halogenations/Lithiations/Fluorine and Fluorination Chemistry
• Suzuki and Other Cross-Coupling Reactions
• Organometallic Chemistry
• Low Temperature Chemistry
• Quality by Design and Process Analytical Technology

• Intermediates
• Surfactants
• Flavors and Fragrances
• Coatings/Pigments
• Agrochemicals
• Initiators
• Bulk Chemicals
• Isocyanate Reactions
• Ethylene Oxide and Propylene Oxide (EO/PO)
• Highly Oxidizing Reactions
• Hydroformylation
• Catalytic Reactions
• Phosgenations
• Esterifications
• Halogenations

The ReactIR 702L is the first system 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.

ReactIR is Ready to Run Overnight!
ReactIR 702L uses solid-state cooling technology to deliver best-in-class performance - without the need for liquid nitrogen. By eliminating hazardous setup and repetitive Dewar refills, scientists can easily monitor chemistry over extended periods.

ReactIR is Ready to Grab and Go!
Small, stackable units save valuable space in the fume hood offers flexibility to deploy ReactIR in various locations across the lab. An “always on“ detector reduces set up time and enables scientists to start collecting data with confidence at a moment‘s notice.

ReactIR is Ready for Your Chemistry!
Probe- and flow-based sampling technologies enable scientists to study liquid and gas phase chemistry in batch or continuous setups. Fit-for-purpose construction materials make data collection straightforward in acidic and corrosive environments across a wide range of temperatures and pressures.

Continuous measurements from infrared spectroscopy are used for obtaining reaction profiles to calculate reaction rates. A list of publications from peer-reviewed journals focuses on exciting and novel applications of in-situ FTIR spectroscopy. Researchers in both academia and industry employ in-situ FTIR spectroscopy to provide comprehensive information and rich experimental data that to advance their research.

Alkylations

• Athavale, S. V., Simon, A., Houk, K. N., & Denmark, S. E. (2020). Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies. Nature Chemistry, 12(4), 412–423. https://doi.org/10.1038/s41557-020-0421-8
• Kariofillis, S. K., Shields, B. J., Tekle-Smith, M. A., Zacuto, M. J., & Doyle, A. G. (2020). Nickel/Photoredox-Catalyzed Methylation of (Hetero)aryl Chlorides Using Trimethyl Orthoformate as a Methyl Radical Source. Journal of the American Chemical Society, 142(16), 7683–7689. https://doi.org/10.1021/jacs.0c02805

Biocatalysis

• Allsop, G. L., Carey, J. S., Joshi, S., Leong, P., & Mirata, M. A. (2020). Process Development toward a Pro-Drug of R-Baclofen. Organic Process Research & Development, 25(1), 136–147. https://doi.org/10.1021/acs.oprd.0c00491
• Pesci, L., Gurikov, P., Liese, A., & Kara, S. (2017). Amine-Mediated Enzymatic Carboxylation of Phenols Using CO2 as Substrate Increases Equilibrium Conversions and Reaction Rates. Biotechnology Journal, 12(12), 1700332. https://doi.org/10.1002/biot.201700332

Chemical Catalysis

• Ren, R., Huang, P., Zhao, W., Li, T., Liu, M., & Wu, Y. (2021). A New ternary organometallic Pd(ii)/Fe(iii)/Ru(iii) self-assembly monolayer: the essential ensemble synergistic for improving catalytic activity. RSC Advances, 11(3), 1250–1260. https://doi.org/10.1039/d0ra09347e
• Wu, X., Ding, G., Lu, W., Yang, L., Wang, J., Zhang, Y., Xie, X., & Zhang, Z. (2021). Nickel-Catalyzed Hydrosilylation of Terminal Alkenes with Primary Silanes via Electrophilic Silicon–Hydrogen Bond Activation. Organic Letters, 23(4), 1434–1439. https://doi.org/10.1021/acs.orglett.1c00111

Chemical Kinetics

• Foth, P. J., Malig, T. C., Yu, H., Bolduc, T. G., Hein, J. E., & Sammis, G. M. (2020). Halide-Accelerated Acyl Fluoride Formation Using Sulfuryl Fluoride. Organic Letters, 22(16), 6682–6686. https://doi.org/10.1021/acs.orglett.0c02566
• Wei, B., Sharland, J. C., Lin, P., Wilkerson-Hill, S. M., Fullilove, F. A., McKinnon, S., Blackmond, D. G., & Davies, H. M. L. (2019). In Situ Kinetic Studies of Rh(II)-Catalyzed Asymmetric Cyclopropanation with Low Catalyst Loadings. ACS Catalysis, 10(2), 1161–1170. https://doi.org/10.1021/acscatal.9b04595

Epoxides

• Anderson, T. S., & Kozak, C. M. (2019). Ring-opening polymerization of epoxides and ring-opening copolymerization of CO2 with epoxides by a zinc amino-bis(phenolate) catalyst. European Polymer Journal, 120, 109237. https://doi.org/10.1016/j.eurpolymj.2019.109237
• Marbach, J., Höfer, T., Bornholdt, N., & Luinstra, G. A. (2019). Catalytic Chain Transfer Copolymerization of Propylene Oxide and CO 2 using Zinc Glutarate Catalyst. ChemistryOpen, 8(7), 828–839. https://doi.org/10.1002/open.201900135

Fluorination

• Morgan, P. J., Hanson-Heine, M. W. D., Thomas, H. P., Saunders, G. C., Marr, A. C., & Licence, P. (2020). C–F Bond Activation of a Perfluorinated Ligand Leading to Nucleophilic Fluorination of an Organic Electrophile. Organometallics, 39(11), 2116–2124. https://doi.org/10.1021/acs.organomet.0c00176
• Turksoy, A., Scattolin, T., Bouayad‐Gervais, S., & Schoenebeck, F. (2020). Facile Access to AgOCF3and Its New Applications as a Reservoir for OCF2for the Direct Synthesis of N−CF3, Aryl or Alkyl Carbamoyl Fluorides. Chemistry – A European Journal, 26(10), 2183–2186. https://doi.org/10.1002/chem.202000116

Halogenation

• Dunn, A. L., Leitch, D. C., Journet, M., Martin, M., Tabet, E. A., Curtis, N. R., Williams, G., Goss, C., Shaw, T., O’Hare, B., Wade, C., Toczko, M. A., & Liu, P. (2018). 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
• Sugiyama, M., Akiyama, M., Nishiyama, K., Okazoe, T., & Nozaki, K. (2020). Synthesis of Fluorinated Dialkyl Carbonates from Carbon Dioxide as a Carbonyl Source. ChemSusChem, 13(7), 1775–1784. https://doi.org/10.1002/cssc.202000090

Hydroformylation

• Hood, D. M., Johnson, R. A., Carpenter, A. E., Younker, J. M., Vinyard, D. J., & Stanley, G. G. (2020). Highly active cationic cobalt(II) hydroformylation catalysts. Science, 367(6477), 542–548. https://doi.org/10.1126/science.aaw7742
• Yu, S. M., Snavely, W. K., Chaudhari, R. V., & Subramaniam, B. (2020). Butadiene hydroformylation to adipaldehyde with Rh-based catalysts: Insights into ligand effects. Molecular Catalysis, 484, 110721. https://doi.org/10.1016/j.mcat.2019.110721

Kinetics

• Hosoya, M., Shiino, G., & Tsuno, N. (2021). A Practical Transferring Method from Batch to Flow Synthesis of Dipeptides via Acid Chloride Assisted by Simulation of the Reaction Rate. Chemistry Letters, 50(6), 1254–1258. https://doi.org/10.1246/cl.210103
• Yang, C., Feng, H., & Stone, K. (2021). Characterization of Propionyl Phosphate Hydrolysis Kinetics by Data-Rich Experiments and In-Line Process Analytical Technology. Organic Process Research & Development, 25(3), 507–515. https://doi.org/10.1021/acs.oprd.0c00451

Lithiation

• 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
• St-Jean, F., Piechowicz, K. A., Sirois, L. E., Angelaud, R., & Gosselin, F. (2018). Study of a Competing Hydrodefluorination Reaction During the Directed ortho-Lithiation/Borylation of 2-Fluorobenzaldehyde. Organometallics, 38(1), 119–128. https://doi.org/10.1021/acs.organomet.8b00730

Polymerization

• Ambrose, K., Murphy, J. N., & Kozak, C. M. (2019). Chromium Amino-bis(phenolate) Complexes as Catalysts for Ring-Opening Polymerization of Cyclohexene Oxide. Macromolecules, 52(19), 7403–7412. https://doi.org/10.1021/acs.macromol.9b01381
• Zhang, D., Zhang, Y., Fan, Y., Rager, M. N., Guérineau, V., Bouteiller, L., Li, M. H., & Thomas, C. M. (2019). Polymerization of Cyclic Carbamates: A Practical Route to Aliphatic Polyurethanes. Macromolecules, 52(7), 2719–2724. https://doi.org/10.1021/acs.macromol.9b00436

Suzuki and Related Cross Coupling Reactions

• Matelienė née Dauksaîtė, L., Knaup, J., von Horsten, F., Gu, X., & Brunner, H. (2020). Benign Arylations of Dimethyl Itaconate via Heck-Matsuda Reaction Utilizing in-Situ Generated Palladium on Aluminum Oxide. European Journal of Organic Chemistry, 2020(1), 127–135. https://doi.org/10.1002/ejoc.201901708
• Reddy, K. S., Siva, B., Reddy, S. D., Naresh, N. R., Pratap, T. V., Rao, B. V., Hong, Y. A., Kumar, B. V., Raju, A. K., Reddy, P. M., & Hu, A. (2020). In Situ FTIR Spectroscopic Monitoring of the Formation of the Arene Diazonium Salts and Its Applications to the Heck–Matsuda Reaction. Molecules, 25(9), 2199. https://doi.org/10.3390/molecules25092199

Synthesis

• Connor, C. G., DeForest, J. C., Dietrich, P., Do, N. M., Doyle, K. M., Eisenbeis, S., Greenberg, E., Griffin, S. H., Jones, B. P., Jones, K. N., Karmilowicz, M., Kumar, R., Lewis, C. A., McInturff, E. L., McWilliams, J. C., Mehta, R., Nguyen, B. D., Rane, A. M., Samas, B., Sitter, B. J. Ward, H. W., & Webster, M. E. (2020). Development of a Nitrene-Type Rearrangement for the Commercial Route of the JAK1 Inhibitor Abrocitinib. Organic Process Research & Development, 25(3), 608–615. https://doi.org/10.1021/acs.oprd.0c00366
• Millward, M. J., Ellis, E., Ward, J. W., & Clayden, J. (2021). Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C–N bonds. Chemical Science, 12(6), 2091–2096. https://doi.org/10.1039/d0sc06188c