FTIR Spectroscopy

What is FTIR Spectroscopy?

FTIR spectroscopy (FTIR) is an analytical methodology that is widely 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 related to the vibrational bond energies of the functional groups present in the molecule.  A characteristic pattern of bands is formed, which is the vibrational spectrum of the molecule.  The position and intensity of these spectral bands provide a fingerprint of molecular structure, making FTIR spectroscopy a highly adaptable and useful technique.  FTIR spectroscopy is a great advance over the traditional dispersive infrared approach for a number of reasons including that the entire FTIR spectrum is collected in a fraction of a second and, by co-adding spectra, signal to-noise is improved.   

What is FTIR Spectroscopy used for?

FTIR spectroscopy has broad use and applicability in the analysis of molecules important in the pharmaceutical, chemical and polymer industries.  FTIR spectroscopy is widely used in industry and academic laboratories to better understand reaction kinetics, mechanism and pathways as well as catalytic cycles.  In QA/QC labs, FTIR spectroscopy is used to ensure that raw materials, intermediate compounds and final products meet content and purity specifications.  In chemical product development, FTIR spectroscopy is used to help scale-up chemical reactions, optimize reaction yield and minimize impurities.  In chemical production, FTIR spectroscopy helps to ensure that processes are stable, in control, and meet end-product specifications and impurity profiles. 

How Does FTIR Spectroscopy Work?

The classic Fourier transform infrared spectrometer consists of several key components – a light source, typically an infrared radiator, an interferometer such as a Michaelson with both fixed and moving mirror, a sample compartment, and a thermal or photonic detector.  Broad band infrared energy from the source is directed onto a beamsplitter, which passes the energy along two different paths.  One path has a fixed mirror at the end; the other a moving mirror.  The infrared energy from these two paths return and recombine at the beamsplitter causing a constructive and destructive interference pattern, the interferogram.  This modulated infrared beam is passed to the sample where it is absorbed as a function of the molecular structure of the sample.  The resultant interferogram is treated with a Fourier transform that converts the intensity vs. time signal into the intensity vs. frequency spectrum.   The single beam sample spectrum is ratioed against a reference spectrum to remove the background contributions, resulting in the typical infrared absorbance/transmission spectrum 

Why Use FTIR Spectroscopy?

In many instances, reaction understanding requires the construction of accurate reaction profiles for each species that are expressed as concentration versus time, leading to the determination of reaction kinetics.  FTIR Spectroscopy is an ideal technique to provide this information, as it allows the rapid collection of detailed reaction profiles.

What advantages does FTIR Spectroscopy bring to reaction analysis?

FTIR Spectroscopy brings a couple of advantages to reaction analysis.  First, the use of the fingerprint region of the mid-infrared enables the individual tracking of chemical species, which in turn provides clues to the mechanism of the reaction.  Second, Beer's Law gives the connection between the measured absorbance of the reaction species and its concentration.  This relationship means we can use an offline measurement to determine the concentration of an offline sample, and then use that data point to scale the mid-infrared profile.  There is a correlation between the concentration measurement of offline samples and the measured shape of the in situ samples.

Why use FTIR Spectroscopy instead of alternative techniques?

Mid-infrared attenuated total reflectance (ATR) technology offers numerous advantages over alternative analytical methods, including other molecular spectroscopy techniques.  Researchers and scientists improve chemical development by leveraging these advantages, including:

• Immersible for direct insertion into reaction vessel for in situ, continuous, real-time measurements
• No extractive sampling required, providing the ability to measure chemistry in its natural environment
• Impervious to bubbles or solids, making it ideal for hydrogenations or any heterogeneous reactions
• Suitable for aqueous chemistry
• Non-destructive, preserving the integrity of the chemical reaction
• Adheres to Beer-Lambert law, enabling both qualitative and quantitative measurements

Instantaneous information can be gained about a reaction from FTIR spectroscopy because it is an in situ technique.  This is a key benefit to obtaining further insights into reaction behavior, particularly where transient species are involved.

Why is the data generated from FTIR Spectroscopy so important?

The reason why the data is so important is because of its continuous nature.  With FTIR Spectroscopy, data collection is automated, typically generating concentration information every minute, even as fast as four times every second.  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 supporting reaction mechanistic theory.  This means that research can progress at an accelerated rate.  In addition, the data is often more accurate than data analyzed by offline techniques as there is no possible alteration of the molecules by preparation for analysis, or by exposing it to an enviroment other than that within the reaction vessel.

FTIR Spectroscopy Applications

FTIR Spectroscopy works in a wide-range of chemistries in which the molecule is infrared active, the chemistry is in solution or off-gas, and the concentration is higher than ~0.1 %. 

Common FTIR Spectroscopy application areas include:

FTIR versus Raman Spectroscopy

A Comparison

Although FTIR Spectroscopy and Raman Spectroscopy are often interchangeable and give complimentary information, there are practical differences that influence which one will be optimal. Most molecular symmetry will allow for both FTIR and Raman activity. In a molecule that contains a center of inversion, IR bands and Raman bands are mutually exclusive (i.e. the bond will either be Raman active or IR active but it will not be both). One general rule is that functional groups that have large changes in dipoles are strong in the IR, whereas functional groups that have weak dipole changes or have a high degree of symmetry and no net dipole change, will be better seen in Raman spectra.

Choose FTIR Spectroscopy when:

• Reactions in which reactants, reagents, solvents and reaction species fluoresce
• Bonds with strong dipole changes are important, e.g., C=O, O-H, N=O
• Reactions in which reagents and reactants are at low concentration
• Reactions in which solvent bands are strong in Raman and can swamp key species signal
• Reactions in which intermediates that form are IR active

Choose Raman when:

• Investigating carbon bonds in aliphatic and aromatic rings are of primary interest
• Bonds that are difficult to see in FTIR (e.g. 0-0, S-H, C=S, N=N, C=C etc.)
• Examination of particles in solution is important (e.g., polymorphism)
• Lower frequency modes are important (e.g., metal-oxygen)
• Reactions in aqueous media are investigated
• Reactions in which observation through a reaction window is easier and safer (e.g., high pressure catalytic reactions, polymerizations)
• Investigating lower frequency lattice modes is of interest
• Investigation of reaction initiation, endpoint, and product stability of biphasic and colloidal reactions

What Industries Use FTIR Spectroscopy?

FTIR Spectroscopy is used in the pharmaceutical, chemical, and petrochemical industries as well as in academic research.

What is FTIR Spectroscopy used for in the Pharmaceutical Industry?

• Organic Synthesis
• Grignard Reactions
• Hydrogenation Reactions
• Crystallization
• Asymmetric Catalysis
• Halogenations
• Enzymatic Catalysis
• Cross Coupling Reactions
• Organometallic Chemistry
• Solution Phase and Heterogeneous Catalysis

What is FTIR Spectroscopy used for in the Chemical Industry?

• Intermediates
• Surfactants
• Flavors and Fragrances
• Coatings/Pigments
• Agrochemicals
• Initiators
• Bulk Chemicals
• Isocyanate Chemistry
• EO/PO
• Highly Oxidizing Reactions
• Hydroformylation
• Catalytic Processes
• Phosgenations
• Esterifications

What is FTIR Spectroscopy used for in Academic Research?

• Metal-Mediated Chemistry
• Catalysis
• C-H Activation
• Mechanistic Studies
• Reaction Kinetics

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 materials of construction make data collection straightforward in acidic and corrosive environments across a wide range of temperatures and pressures.

This paper presents five examples taken from recent journal articles in which in situ FTIR spectroscopy accomplishes tasks that would be difficult, impossible, or overly time consuming, if carried out with traditional offline techniques:

• Reveal Reaction Mechanisms - Transient Intermediate Detection in a Coupling Reagent
• Monitor Difficult to Sample Chemistry - Lithiation Reaction Performed at -70 °C
• Track Reaction Progress for Better Yield & Purity - Determination of Optimal Reaction Endpoint
• Eliminate Hold Time to Increase Quality & Throughput - Decomposition Leading to Epimerization
• Quickly Determine Kinetics - 1st Order Reaction Kinetics in One Experiment

FTIR Spectroscopy in Recent Journal Publications

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 mid-FTIR spectroscopy to provide comprehensive information and rich experimental data that to advance their research.

Featured FTIR Spectroscopy Citations

• Beutner, G., Young, I., Davies, M., Hickey, M., Park, H., Stevens, J., Ye, Q., “TCFH−NMI: Direct Access to N‑Acyl Imidazoliums for Challenging Amide Bond Formations”, Org. Lett. (2018) 20, 4218−4222.
• Sheikh,N., Leonori,D., Barker,G., Firth,J., Campos,K., Meijer, A., O’Brien,P., Coldham,I., “An Experimental and in Situ IR Spectroscopic Study of the Lithiation−Substitution of N-Boc-2-phenylpyrrolidine and -piperidine: Controlling the Formation of Quaternary Stereocenters” J. Am. Chem. Soc.( 2012) 134, 5300−5308.
• Hamilton, P., Sanganee, M., Graham, J., Hartwig, T., Ironmonger, A., Priestley, C., Senior, L., Thompson, D., Webb, M., “Using PAT To Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical Intermediate”, Org. Process Res. Dev. (2015) 19, 236−243.
• Chanda, A., Daly, A., Foley, D., LaPack, M., Mukherjee, S., Orr, J., Reid, G., Thompson, D., Ward, H., “Industry Perspectives on Process Analytical Technology: Tools and Applications in API Development”, Org. Process Res. Dev. (2015) 19, 63−83.
• Rehbein, M., Husmann, S., Lechner, C., Kunick, C., Scholl, S., “Fast and calibration free determination of first order reaction kinetics in API synthesis using in-situ ATR-FTIR”, European Journal of Pharmaceutics and Biopharmaceutics 126 (2018) 95–100.