Synthesis Reactions

Synthesis reactions are reactions that occur when two different atoms or molecules interact to form a different molecule or compound. Most of the time, when a synthesis reaction occurs, energy is released and the reaction is exothermic. However, an endothermic outcome is also possible. Synthesis reactions are one of the major classes of chemical reactions, which include single displacement, double displacement, and combustion reactions.

Many synthesis reactions are far more complex than the above reaction: A + B → C. For example, organic synthesis reactions may involve more than two different molecules, and mixtures of products can occur along with unreacted starting materials. Intermediate molecules may form that can lead to the formation of byproducts. In addition, depending on how the two colliding reactant molecules orient, both the desired product and byproducts may form - which may effect product purity.

There are various types of synthesis reactions. For example, nucleophilic and electrophilic addition and substitution reactions are broad reaction types that yield innumerable examples of synthesis reactions.

When two or more reactants combine to form a more complex molecule, the composition of the final reaction mixture is dependent on the conditions at which the reaction is carried out. 

A successful synthesis reaction maximizes the creation of desired molecules and minimizes byproduct molecules. A thorough understanding of reaction kinetics, mechanism, and effect of reaction variables are keys to successful synthesis reactions.

• Quality of Reactants, Reagents, and Catalysts - The quality and purity of starting materials and stable sources/vendors of those materials is key to successful, reproducible synthesis reactions and processes.
  
  
• Reaction Conditions - Since synthesis reactions are sensitive to reaction parameters, such as temperature, pressure, agitation rate, and dosing rate, precise and accurate control of these variables is crucial to the successful outcome. EasyMax chemical synthesis reactor provides automated parameter control, accuracy, and precision of reaction parameters.
  
  
• Reaction Equipment - In the pharmaceutical industry, most synthesis reactions run in batch mode. The physical configuration of EasyMax reactors are an improvement over the classic round bottom flask due to surface area and agitation efficiency considerations.  Continuous flow processes are rapidly becoming more frequently used, and ReactIR technology accommodates the real-time analysis of continuous flow and batch syntheses.
  
  
• Reaction Kinetics - A thorough understanding of reaction rates are crucial to ensure optimized product yield and minimum byproducts. Through data-rich experiments, ReactIR simplifies and speeds the measurement of kinetic factors in synthesis reactions.
  
  
• Product Isolation/Purity - Though separation techniques are a mainstay for product isolation and purity, an understanding 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 important, a thorough understanding and control of crystallization via ParticleTrack and ParticleView technology is critical to ensuring purity and ease of isolating desired products.
  
  
• Safety - Commercially-important chemistry requires lab-to-plant protocols that provide optimized yield, acceptable impurity profiles, and safe operation. ReactIR advances reaction scale-up by elucidating the effects of reaction variables on overall synthesis performance. Reaction calorimetry ensures safe reactions from screening through scale-up to process by measuring heats of reaction. ReactIR in situ analytics 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.

Individually, or as an integrated chemical workstation, these tools provide critical support for better synthesis reactions:

• Chemical Synthesis Reactors (EasyMax and OptiMax)
  Unattended, precise control and data collection of reaction conditions
  
• FTIR Spectrometers and Raman Spectrometers
  Real-time tracking and profiling of key reaction species as a function of reaction time to aid kinetics and mechanistic investigations
  
• Automated, Inline Sampling (EasySampler)
  Unattended, representative sampling of reactions when offline analysis is required
  
• EasyViewer
  In-situ video microscopy of particle/droplet size and shape to quickly increase purity and yield during work-up
• Powerful Analytical Software (iC)
  Integrates data streams for comprehensive understanding and data management

Smart chemical synthesis reactors, combined with unattended dosing and automated sampling, provide a simple and safe way to precisely control reaction parameters and obtain reaction information unattended and around the clock.

• Automatically record recipe steps, experimental conditions and analytical data making it easy to repeat experiments and share findings with colleagues
  
• Run reactions at any temperature from -90°C to 180°C without an ice bath, oil bath, or heating mantle
  
• Configure parameter controls (such as temperature, dosing, sampling, and stirring) separately for each vessel
  
• For multi-parameter analysis, including Design of Experiments (DoE) studies, precise and reproducible control help to yield accurate results 
  
• Interchangeable sleeves, glass reactors, and tubes provide flexibility to synthesize at volumes from 0.5 mL to 1000 mL
  
   

Gain in-depth information about reaction kinetics, mechanisms, and pathways.  Support safe and optimized scale-up of chemistry.  ReactIR and ReactRaman spectrometers provide in situ, real-time monitoring of chemical reactions for batch and continuous flow syntheses. 

• Develop real-time trending profiles for key reaction species: reactants, intermediates, products, and byproducts
• 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, and endpoint. Detect reaction stalling or upsets
• Rapidly determine the effect of variables on reactions
• Investigate the broadest range of chemical reactions with ReactIR and ReactRaman.  Choose the best technique to match specific chemistries and reaction variables. 
• Enhance understanding of solution crystallization processes with ReactRaman for monitoring crystallographic form and polymorphism, and ReactIR for investigating solvent effects and supersaturation. 

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EasySampler is an automated, unattended technology delivering representative and reproducible samples. The probe-based technology has a micro-pocket, which takes samples at any given time, quenches in-situ and dilutes for ready to analyze offline samples. 

EasySampler supports reaction understanding by providing samples on demand. Sampling is performed under reaction conditions, making it truly representative. The samples, once collected and time stamped, can be analyzed via offline analytical methods and the result integrated back into the data stream. An additional value lies in the increased data quality through automatic and seamless data collection. The increased accuracy and precision of automated sampling provides higher quality versus manual sampling. 

• Polymerization Reactions
• Organometallic Chemistry
• Metal-Catalyzed Reactions
• Flow Chemistry
• Design of Experiments (DoE)
• Low Temperature Chemistry
• Elevated Pressure Chemistry (Hydrogenation Reactions)
• Enzyme Catalyzed Reactions Biocatalysis
• Oligonucleotide Synthesis

Below is a selection of publications where automated solutions are used for synthesis reactions.

• Yang, H. S., Macha, L., Ha, H. J., & Yang, J. W. (2021). Functionalisation of esters via 1,3-chelation using NaOtBu: mechanistic investigations and synthetic applications. Organic Chemistry Frontiers, 8(1), 53–60. https://doi.org/10.1039/d0qo01135e
• 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
• Jurica, J. A., & McMullen, J. P. (2021). Automation Technologies to Enable Data-Rich Experimentation: Beyond Design of Experiments for Process Modeling in Late-Stage Process Development. Organic Process Research & Development, 25(2), 282–291. https://doi.org/10.1021/acs.oprd.0c00496
• Shi, Y., Prieto, P. L., Zepel, T., Grunert, S., & Hein, J. E. (2021). Automated Experimentation Powers Data Science in Chemistry. Accounts of Chemical Research, 54(3), 546–555. https://doi.org/10.1021/acs.accounts.0c00736
• 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., . . . 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
• Glace, A. W., Cohen, B. M., Dixon, D. D., Beutner, G. L., Vanyo, D., Akpinar, F., Rosso, V., Fraunhoffer, K. J., DelMonte, A. J., Santana, E., Wilbert, C., Gallo, F., & Bartels, W. (2020). Safe Scale-up of an Oxygen-Releasing Cleavage of Evans Oxazolidinone with Hydrogen Peroxide. Organic Process Research & Development, 24(2), 172–182. https://doi.org/10.1021/acs.oprd.9b00462
• Benkovics, T., McIntosh, J., Silverman, S., Kong, J., Maligres, P., Itoh, T., Yang, H., Huffman, M., Verma, D., Pan, W., Ho, H. I., Vroom, J., Knight, A., Hurtak, J., Morris, W., Strotman, N., Murphy, G., Maloney, K., & Fier, P. (2020). Evolving to an Ideal Synthesis of Molnupiravir, an Investigational Treatment for COVID-19. ChemRxiv. Published. https://doi.org/10.26434/chemrxiv.13472373.v1
• Mennen, S. M., Alhambra, C., Allen, C. L., Barberis, M., Berritt, S., Brandt, T. A., Campbell, A. D., Castañón, J., Cherney, A. H., Christensen, M., Damon, D. B., Eugenio de Diego, J., García-Cerrada, S., García-Losada, P., Haro, R., Janey, J., Leitch, D. C., Li, L., Liu, F., . . . Zajac, M. A. (2019). The Evolution of High-Throughput Experimentation in Pharmaceutical Development and Perspectives on the Future. Organic Process Research & Development, 23(6), 1213–1242. https://doi.org/10.1021/acs.oprd.9b00140
• Wang, K., Han, L., Mustakis, J., Li, B., Magano, J., Damon, D. B., Dion, A., Maloney, M. T., Post, R., & Li, R. (2019). Kinetic and Data-Driven Reaction Analysis for Pharmaceutical Process Development. Industrial & Engineering Chemistry Research, 59(6), 2409–2421. https://doi.org/10.1021/acs.iecr.9b03578

Calow, A. D. J., Carbó, J. J., Cid, J., Fernández, E., & Whiting, A. (2014). Understanding α,β-Unsaturated Imine Formation from Amine Additions to α,β-Unsaturated Aldehydes and Ketones: An Analytical and Theoretical Investigation. The Journal of Organic Chemistry, 79(11), 5163–5172. 

In previous work, the researchers had reported a catalytic method to synthesize chiral γ-amino alcohols via in situ generation of α,β-unsaturated imines. They stated that there was a lack of kinetic or mechanistic studies regarding the relative 1,2- versus 1,4- addition of primary amines to α,β-unsaturated aldehydes and ketones. To further this understanding, the researchers used in situ ReactIR spectroscopy along with NMR studies and DFT calculations, to better characterize the addition of primary amines to α,β-unsaturated aldehydes and ketones (1,2- vs 1,4-addition) and examine the relative rates of these reactions.

ReactIR data showed that when benzylamine was added to crotonaldehyde, 1,2- addition resulted exclusively whereas when benzylamine was added to methyl vinyl ketone, 1,4- addition resulted exclusively.

This white paper, COVID-19 Recovery in Chemical R&D – Journey to the New Normal, discusses the implications of the global pandemic, as well as how scientists in organizations that made investments in automation for understanding and controlling processes were able to remain agile and productive during site restrictions and closures.