Synthesis Reactions

What is a Synthesis Reaction?

In the simplest cases, a synthesis reaction occurs 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 but are not limited to, single displacement, double displacement, and combustion reactions.

Complex Synthesis Reactions

Many synthesis reactions are far more complex than 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. This general type of reaction is perhaps the most common in chemistry. 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. 

Factors Influencing Synthesis Reactions

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 accomodates 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.

Synthesis Reaction Examples

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

Tools to Optimize Synthesis Reactions

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
  
• Powerful Analytical Software (iC)
  Integrates data streams for comprehensive understanding and data management

Enhance Understanding of Synthesis Reactions with FTIR & Raman

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. 

In Situ Spectroscopy for Synthesis Reactions in Industry-Related Publications

Below is a selection of publications where in situ spectroscopy is used for synthesis reactions.

• Squitieri, R., Shearn-Nance, G., Hein, J., Shaw, J., “Synthesis of Esters by in Situ Formation and Trapping of Diazoalkanes”, J. Org. Chem. 2016, 81, 5278−5284.
• Alison R. Schultz, Sachin Bobade, Philip J. Scott, and Timothy E. Long, “Hydrocarbon-Soluble Piperazine-Containing Dilithium Anionic Initiator for High Cis-1,4 Isoprene Polymerization”, Macromol. Chem. Phys. 2018, 219, 1700201.
• Darren Willcox, Ryan Nouch, Alexander Kingsbury, David Robinson, Joe V. Carey, Steve Brough, and Simon Woodward, “Kinetic Analysis of Copper(I)/Feringa-Phosphoramidite Catalyzed AlEt3 1,4-Addition to Cyclohex-2-en-1-one”, ACS Catal. 2017, 7, 6901-6908.
• Alyssa M. Hua, Duy N. Mai, Ramon Martinez, and Ryan D. Baxter “Radical C-H Fluorination Using Unprotected Amino Acids as Radical Precursors”, Org. Lett., 2017, 19 (11), pp 2949–2952.
• K. Michael Schäfer, Leonie Reinders, Jan Fiedler, and Mark R. Ringenberg “Twisting and Tilting 1,1'-Bis(dialkylphosphino) ferrocene Bound to Low Valent Tricarbonylmaganese(I to -I)”, Inorg. Chem. 2017, 56, 14688-14696.
• Alison R Schultz, Mingtao Chen, Gregory B Fahs, Robert B Moore and Timothy E Long, “Living Anionic Polymerization of 4-Diphenylphosphinostyrene for ABC Triblock Copolymers”, Polym. Int. 2017, 66, 52–58.
• Noriki Kutsumura, Yasuaki Koyama, Yuko Suzuki, Ken-ichi Tominaga, Naoshi Yamamoto, Tsuyoshi Saitoh, Yasuyuki Nagumo, and Hiroshi Nagase, “Favorskii-Type Rearrangement of the 4,5-Epoxymorphinan Skeleton”, Org. Lett. 2018, 20, 1559-1562.
• Justin R. Griffiths, Elan J. Hofman, Jerome B. Keister, and Steven T. Diver, “Kinetics and Mechanism of Isocyanide-Promoted Carbene Insertion into the Aryl Substituent of an N‑Heterocyclic Carbene Ligand in Ruthenium-Based Metathesis Catalysts”, Organometallics 2017, 36, 3043-3052.

Featured Article: Understanding α,β-Unsaturated Imine Formation

Determine Relative Reaction Rates and Further Mechanistic Understanding

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.

Calow, A., Carbó, J., Cid, J., Fernández, E., Whiting, A., “Understanding α,β-Unsaturated Imine Formation from Amine Additions to α,β-Unsaturated Aldehydes and Ketones: An Analytical and Theoretical Investigation”, J. Org. Chem. 2014, 79, 5163−5172. https://doi.org/10.1021/jo5007366

Replace Manual Synthesis Reaction Steps

With Automated Synthesis Workstations

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 -40 °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, such as Design of Experiments (DoE), 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
  
   

Automated Workstations for Synthesis Reactions in Industry-Related Publications

Below is a selection of publications where automated workstations were used for synthesis reactions.

• Mills J. E., Drug Evaluation − Chemical Development, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, Spring House, PA 19440-0776, 2004.
  
• Owen et al., Organic Process Research & Development, 2001, 5, pp. 308 − 323.
  
• Lewis G. A., Mathieu D., Phan-Tan-Luu R. − Pharmaceutical Experimental Design, Dekker Inc., New York.
  
• Hwang R., Noack R. M. − International Journal of Experimental Design and Process Optimisation, 2011, Vol.2, No.1, pp. 58 − 65.
  
• Guidance for Industry, Q8 (R2) Pharmaceutical Development, U.S. Department of Health and Human Services, Food and Drug Administration, November 2009, Revision 2.
  
• Charles D. Papageorgiou et al. "Development and Scale-up of an Efficient Miyaura Borylation Process Using Tetrahydroxydiboron" Org. Process Res. Dev. 2017, 21, 65-74.
  
• Thomas, et al. "Scalable and Selective Preparation of 3, 3′, 5, 5′-Tetramethyl-2, 2′-biphenol." Organic Process Research & Development 21.1 (2016): 79-84.
  
• Buetti-Weekly, Michele T., et al. "Development of a safe and scalable process for the preparation of allyl glyoxalate." Organic Process Research & Development 22.1 (2017): 82-90.
  
• Yang., et al. "Evaluation of Potential Safety Hazards Associated with the Suzuki−Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species." Org. Process Res. Dev. 2018, 22, 351−359.
  

Free White Paper: A New Synthesis Lab

Innovation is challenging when equipment limits experiment possibilities. The complexity of synthesis reactions increases every day. This white paper discusses how chemists are responding with innovative techniques:

• Automated Reaction Planning and Execution
• Complete Data Capture for Every Experiment
• Synthesis Tools that Solve Common Experimental Problems

To learn how smart synthesis tools combined with lab digitalization capabilities can transform chemical development, download the white paper: The Modern Synthesis Lab: A New Workplace for Chemists.