Chemical Synthesis

Chemical synthesis describes the physico-chemical transformation that occurs when two or more simpler molecules combine in a controlled fashion to produce a more complex chemical product. Often chemical synthesis is far more complex than A+B = C, and mixtures can occur containing product(s) and by-products.

Chemical synthesis is employed in the development of all commercially important products in pharmaceutical, polymer, fine and bulk chemical industries. The success of a chemical synthesis, which is defined as producing the target molecule with the correct economies and quality, is related to a efficient use of reactants and reagent via a thorough understanding and control of reaction variables. 

Modern chemical synthesis is responsible for all of the manufactured organic- and inorganic-based products that are developed to benefit civilization. Modern chemical synthesis requires that processes are well-understood, well-controlled, and produce results that meet economic, quality and safety objectives, while at the same time minimizing environmental impact.

Modern chemical synthesis employs sophisticated hardware and software to ensure the fundamental objectives of quality, safety, and yield are met. These tools extend from chemical development, where an understanding of reaction kinetics, thermodynamics, and the effect of reaction variables is fully characterized, to manufacturing where quality control and process stability are the keys to economic success. 

The chemical synthesis lab has undergone significant changes in fairly recent years. The classic analog tools of chemical synthesis, such as round bottom flasks, heating mantles, cooling baths, stirring devices are rapidly being replaced by precise, digitally controlled synthesis technology such as automated laboratory reactors that result in far more reproducible reaction control.

The manner in which chemistry is performed is changing, as well. Classical chemical batch reactions are being replaced by continuous flow reactions that offer better yield, higher quality and safer reactions. In support of these new approaches to performing chemical synthesis, analytical equipment in the chemical synthesis lab has also changed. Offline, manual, wet chemical, and chromatography methods are rapidly giving way to online or inline real-time analysis. This direction of moving away from single point, offline measurement to data-rich, real-time analysis, supports one of the major trends in modern chemical synthesis – Quality by Design (QbD). 

Modern chemical synthesis in both lab and production requires advanced technologies that meet the new requirements of quality, safety, and productivity. EasyMax chemical synthesis reactor, often equipped with calorimetric capability, is used in pharmaceutical and chemical development laboratories to optimize reaction variables, for faster scale-up, for measuring reaction thermodynamics and to ensure process safety. The automated laboratory reactor is a superior technology to support Design of Experiment (DoE) applications and other methods that mathematically relate experimental parameters and performance.

When particle size, form, and distribution are crucial, EasyViewer and ParticleTrack particle size analyzers are often used in conjunction with EasyMax. When offline testing is required,  EasySampler automatically removes a reaction sample at pre-selected times and quench/dilutes it under reaction conditions for HPLC or other analyses.  EasySampler operates unattended 24/7 and does not interrupt the reaction or affect reaction conditions.  For real-time, in situ analysis, ReactIR and Raman spectrometer measurements are used for determining reaction kinetics, overall reaction progress, and to support proposed reaction mechanisms.  These spectroscopic technologies provide a critical analytical data stream in both batch and continuous flow applications. 

• Quality of Reactants, Reagents, and Catalysts – The quality of starting materials and stable sources/vendors of those materials is key to successful, reproducible synthesis reactions and processes.
  
  
• Reaction Conditions – Since chemical synthesis reactions are sensitive to parameters such as reaction temperature, pressure, agitation rate and dosing rate, precise and accurate control of these variables is crucial to a successful outcome. EasyMax provides automated parameter control, accuracy, and precision of reaction variables.
  
  
• Reaction Equipment – In the pharmaceutical industry, most chemical syntheses are performed in batch mode, but continuous flow processes are becoming increasingly more frequent. The bulk chemical industry has used continuous flow processes for years. ReactIR in situ analysis supports both batch and continuous flow syntheses. The physical configuration of EasyMax reactors are an improvement over the classic round bottom flask due to surface area and agitation efficiency considerations
  
  
• Reaction Kinetics – A thorough understanding of reaction rates are crucial to ensure optimized product yield and minimum by-products. Through data-rich experiments, in situ analyses via ReactIR and ReactRaman simplify and speed the measurement of kinetic factors in synthesis reactions, as well as provides support for proposed reaction mechanisms.  When off-line analysis is preferable, EasySampler automatically removes a sample from the reaction mixture at pre-selected times and quench/dilutes it for HPLC or other analyses. EasySampler removes the sample without interrupting the synthesis or disturbing reaction conditions. 
  
  
• Product Isolation/Purity – Though advanced separation techniques are a mainstay for product isolation and purity, a thorough understanding of the effect of reaction variables to reduce the presence of impurities that may be difficult to separate for product is important. By optimizing reaction variables, ReactIR with EasyMax aid impurity reduction. As equally important, a thorough understanding and control of crystallization via ParticleTrack and EasyViewer technology is critical to ensuring purity and ease of isolating desired products.
  
  
• Safety – Commercially-important chemical synthesis requires lab-to-plant protocols that provide both optimized yield, acceptable impurity profiles, and safe operation. ReactIR advances reaction scale-up by elucidating the effects of reaction variables on overall chemical synthesis performance. Calorimetry ensures safe reactions from screening, through scale-up to process by measuring heats of reaction. ReactIR minimizes exposure of scientists and technicians to toxic chemicals and potentially hazardous reactions by eliminating grab sampling for offline analysis. When offline analysis is required, EasySampler provides automated, in situ sampling and dilution of samples for HPLC, eliminating worker exposure.

• Chemical Reactors - for precise, automated control of reaction parameters
  
  
• ReactIR and ReactRaman Spectrometers – real-time tracking and profiling of key reaction species as a function of reaction time to aid kinetics and mechanistic investigations
  
  
• EasySampler – automated sampling of reactions when offline analysis is required
  
  
• Particle Size Analyzers – in situ monitoring and measurement of crystals, particles, and crystallization processes

Individually, or as an integrated chemical workstation, provides critical support for better synthesis reactions.

Process Development and Scale-up workstations provide thermodynamic data in real time, the ability to investigate the impact of changing conditions on heat and mass transfer and support studies related to concentrations, temperature, or kinetics. Reaction calorimeters allow researchers to measure heat generated by a reaction and to control the reaction based on heat output. The control of the relevant parameters including additions can be automated and pre-programmed, so experiments can be safely run while recording all reaction parameters, 24 hours a day. The individual steps of the process of the polymerization reaction together with the experimental data are continuously recorded and stored securely making them available for evaluation and interpretation. Due to the safe, highly accurate, and precise measurement and control, the number of experiments required is reduced – making scale-up efficient.

EasySampler provides representative samples over the entire reaction. Accurate, reproducible, and representative samples provide high-quality HPLC results. This makes it easy to study reaction kinetics and develop impurity profiles, even from heterogeneous mixtures, air- and moisture-sensitive reactions, and reactions under pressurize and toxic conditions. At user-defined time points, EasySampler automatically captures reaction samples, quenches samples immediately and at reaction conditions, and finally dilutes the sample to a user-specified concentration. 

The infrared spectrometer for real-time monitoring of chemical reactions directly in the reaction vessel or flow reactor. Gain in-depth information about reaction kinetics, mechanism and pathways.

• Develop real-time trending profiles for key reaction species: reactants, intermediates, products, by-products
  
  
• Obtain data-rich information for traditional kinetic analysis or Reaction Progress Kinetics Analysis (RPKA) methods
  
  
• Monitor reactions where removing a sample for offline analysis is difficult, impossible or undesirable – low temperature, elevated temperature/pressure, viscous, toxic reagents, highly energetic reactions, air/moisture sensitive, transient intermediates
  
  
• Investigate key stages of a reaction or process such as reaction start, induction period, accumulation, conversion, endpoint. Detect reaction stalling or upset.

Niklas O. Thiel, Benyapa Kaewmee, Trung Tran Ngoc, Johannes F. Teichert, “A Simple Nickel Catalyst Enables Broad E-Selective Alkyne Semihydrogenation,” Chem. Euro J.

The authors use nickel catalyst [NiI₂] and 1,1'bis(diphenylphosphino)ferrocene (dppf)] to perform E-selective alkyne semihydrogenations on a range of substrates with a variety of aryl and alkyl substitution patterns. They show that this commercially available nickel catalyst enables the E‐selective alkyne semihydrogenation of a broad range of substituted alkynes.

 ReactIR measurements performed under 30 bar H₂ provided kinetic data and support for proposed mechanism. Initially Z-selective alkyne semihydrogenation occurs as the reaction vessel is warming. Formation of E-stilbene is observed when the temperature reaches 80C after 90 minutes, and after several hours the E-stilbene is the major product. The ReactIR data suggests that two different mechanisms occur. The first mechanism leads to the Z-selective alkyne semihydrogenation; the second is a Z to E isomerization mechanism, associated with Ni hydride intermediates. 

Wen Tian, Rongrong Hu, and Ben Zhong Tang, “One-Pot Multicomponent Tandem Reactions and Polymerizations for Step-Economic Synthesis of Structure-Controlled Pyrimidine Derivatives and Poly(pyrimidine)s”, Macromolecules 2018, 51, 9749−9757.

The researchers report the development of one-pot multicomponent tandem polymerization reactions (MCTP) that enable the synthesis of conjugated poly(pyrimidine)s with specific properties. They show that the polymerizations are performed using a diyne, guanidine HCl, DMSO and O₂ in the presence of CuCl, Cs₂CO₃ and N,N,N’,N’-tetramethylethylenediamine.

In situ FTIR experiments provided data for determining reaction kinetics and MCPT reaction time optimization parameters. ReactIR tracks key species in MCTP of P1 (under air) and P2 (under nitrogen) as a function of time. In the former, band at 1662 cm-1 increases due to formation of carbonyl group; in the latter band at 1662 cm-2 decreases since a carbonyl functionality is not present.

Kallakuri Suparna Rao, Frédéric St-Jean, and Archana Kumar, “Quantitation of a Ketone Enolization and a Vinyl Sulfonate Stereoisomer Formation Using Inline IR Spectroscopy and Modeling”, Org. Process Res. Dev. 2019, 23, 945−951.

The authors report using ReactIR to study the formation of an important vinyl sulfonate intermediate in an API, which has an acyclic tetrasubstituted all-carbon olefin. Via univariate and multivariate modeling, the in situ ReactIR data enabled real-time monitoring of the consumption and quantitative conversion of the ketone, the formation of the metal enolates, as well as quantitation of a minor stereoisomer in a product mixture of tetrasubstituted vinyl sulfonate stereoisomers. The models were validated using IR data acquired over a range of experimental conditions

To optimize the quantitative results, the ReactIR probe was used in combination with an EasyMax automated lab reactor in order to ensure precise control over parameters such as temperature, stirring rate and reaction time.

• Si-min Yu, William K. Snavely, Raghunath V. Chaudhari, Bala Subramaniam, “Butadiene hydroformylation to adipaldehyde with Rh-based catalysts: Insights into ligand effects”, Mol.Catal., 2020, 484, 110721.
• Ryan Nouch, Simon Woodward, Darren Willcox, David Robinson, William Lewis, "Mechanistic-Insight-Driven Rate Enhancement of Asymmetric Copper-Catalyzed 1,4-Addition of Dialkylzinc Reagents to Enones”, Organometallics 2020, March 3, 2020, https://doi.org/10.1021/acs.organomet.0c00005.
• Reni Grauke, Rahel Schepper, Jabor Rabeah , Roland Schoch, Ursula Bentrup, Matthias Bauer, Angelika Brückner, “Impact of Al Activators on Structure and Catalytic Performance of Cr Catalysts in Homogeneous Ethylene Oligomerization – A Multitechnique in situ/operando Study”, 23 October 2019, https://doi.org/10.1002/cctc.201901441.
• Drew M. Hood, Ryan A. Johnson, Alex E. Carpenter, Jarod M. Younker, David J. Vinyard, George G. Stanley, “Highly active cationic cobalt(II) hydroformylation catalysts”, Science, 2020, 367(6477), 542-548.
• Anne-Marie Dechert-Schmitt, Michelle R. Garnsey, Hanna M. Wisniewska, James I. Murray, Taegyo Lee, Daniel W. Kung, Neal Sach, and Donna G. Blackmond, “Highly Modular Synthesis of 1,2-Diketones via Multicomponent Coupling Reactions of Isocyanides as CO Equivalents”, ACS Catal. 2019, 9, 4508−4515.
• Michaela Wernik, Peter Poechlauer, Christoph Schmoelzer, Doris Dallinger, C. Oliver Kappe, “Design and Optimization of a Continuous Stirred Tank Reactor Cascade for Membrane-Based Diazomethane Production: Synthesis of α‑Chloroketones”, Org. Process Res. Dev. 2019, 23, 1359−1368.
• Kori A. Andrea, Francesca M. Kerton, “Triarylborane-Catalyzed Formation of Cyclic Organic Carbonates and Polycarbonates”, ACS Catal., 2019, 9, pp 1799–1809.
• Thibault E. Schmid, Carine Robert, Vincent Richard, Sumesh K. Raman, Vincent Guérineau, Christophe M. Thomas, “Aluminum‐Catalyzed One‐Pot Synthesis of Polyester‐b‐Polypeptide Block Copolymers by Ring‐Opening Polymerization”, Macromol. Chem. and Phys., 2019, 220(14), https://doi.org/10.1002/macp.201900040.
• Niklas O. Thiel, Benyapa Kaewmee, Trung Tran Ngoc, Johannes F. Teichert, “A Simple Nickel Catalyst Enables Broad E-Selective Alkyne Semihydrogenation”, ChemRxiv, 23/08/2019 doi.org/10.26434/chemrxiv.9715955.v1.
• Jeanne Masson-Makdissi, Young Jin Jang, Liher Prieto, Mark S. Taylor, Mark Lautens, “Rhodium-Catalyzed Tandem Isomerization−Allylation: From Diallyl Carbonates to α‑Quaternary Aldehydes”, ACS Catal. 2019, 9, 11808−11812.