The heat of reaction, or reaction enthalpy, is an essential parameter to safely and successfully scale-up chemical processes. The heat of reaction is the energy that is released or absorbed when chemicals are transformed in a chemical reaction. It describes the change of the energy content when reactants are converted into products. While a reaction can be exothermic (heat releasing) or endothermic (heat absorbing), most of the reactions performed in the chemical and pharmaceutical industries are exothermic. Among others, the heat of reaction is one of the thermodynamic properties used in chemical development, scale-up, and safety to scale processes from the lab scale to manufacturing. The heat of reaction or reaction enthalpy is typically expressed as molar enthalpy in kJ/mol, or as specific enthalpy in kJ/kg or kJ/L.
What Is the Heat of Reaction?
Why Do I Need to Understand the Heat of Reaction?
For quite some time, safety considerations have become an essential component of chemical process development, and safety concepts are routinely developed while designing the pilot or large scale process. Industrial associations and federal authorities, such as CSB, OSHA (US), HSE (UK), EU-OSHA, EPSC (EU) or IPE and the State Administration of Work Safety (SAWS) in China, require chemical and pharmaceutical industries to comply with regulations that assure safe production. The directives provided focus on avoiding incidents and accidents in the chemical and pharmaceutical industries.
Risk assessment requires key chemical data that describes the properties of the substances, but also information about the process itself. Among other thermal information, the heat of reaction is an essential parameter that can be used to derive information related to safe processes and to build up process safety knowledge. Building process safety knowledge also means understanding both the desired and possible undesired reactions. While the undesired reaction is primarily concerned with identifying possible side or consecutive reactions that may be followed by a runaway reaction, the investigation of the desired reaction demonstrates how the reaction behaves under normal operating conditions.
The accumulation of starting material, the heat of reaction, the enthalpy of reaction and the specific heat are some of the key parameters necessary to create cooling failure scenarios of the desired reaction. However, more advanced studies, such as the evaluation of worst case scenarios, criticality class or the criticality matrix, use the information from the heat of reaction to the same extent.
How Do You Calculate the Heat of Reaction or Reaction Enthalpy?
The heat of reaction can be calculated based on the standard heat of formation of all reactants involved. However, it is usually determined by measuring the heat production over time using a reaction calorimeter, such as a heat flow calorimeter.
The determination of the heat of reaction requires the knowledge of the overall heat flow balance, including the heat flow through the reactor wall, the amount of heat that is exchanged during dosing of reactants or solvents and the heat that is accumulated due to a temperature increase or decrease.
While the heat release rate and the heat of reaction provide information how the heat is released in function of time, the heat of reaction enthalpy is obtained by integrating the heat of reaction trend between start and end of the reaction. As all of the individual heat flow terms are relevant for the overall heat balance, care has to be taken to determine them as accurately as possible.
Heat of Reaction of Chemical Reactions
Is My Chemistry Exothermal?
The quantity of heat of reaction depends on the reactants and the products formed and is therefore a function of the strength of the bonds between the atoms which are broken and newly formed.
If the sum of the heat of formation of the reactants is larger than the heat of formation of the products, the reaction is exothermal or heat releasing.
In other words, the heat of reaction varies with the type of reaction and the functional groups involved. While the heat of reaction is around 50 to 70 kJ/mol for a typical esterification reaction, it may be as much as 300 to 600 kJ/mol for hydrogenation reactions of nitro compounds.
Decomposition reactions (e.g. the decomposition of explosives) are much more powerful than any of the typical chemical reactions applied in the chemical and pharmaceutical industry. The heat of reaction of such decomposition reactions, also called heat of detonation, is between 4 and 7.5 MJ/kg of material.
While the heat of reaction of any standard chemical reaction can easily be determined in a reaction calorimeter, the heat of decomposition reactions are either determined using mathematical models or with equipment, such as differential screening calorimeters (DSC), bomb calorimeters or so-called detonation calorimeters.
Heat of Reaction vs. Heat Release Rate
Consistent Data Supporting Safe Scale-up
The heat of reaction describes the exchange of the total amount of energy when reactants are converted into products. However, the heat release rate considers how the energy is released as a function of time and is expressed in W or J/s.
This is of fundamental importance, because the total enthalpy of the reaction may not be critical, but the rate at which that energy is released can make the difference between a safe process and a dangerous one.
Most batch or semi-batch reactors in manufacturing are capable of removing between 25 and 35 W/L, depending on size and cooling concept. Thus, the heat release rate of a chemical process needs to be designed to be within a certain range of heat production rate to ensure that the reaction can be run safely, irrespective of the total heat of reaction.
The Value of the Heat of Reaction in Process Safety
The quantity of the heat of reaction is directly linked to the severity in case of an incident, and finds particular use in the assessment of reactions, scale-up and process safety-related calculations.
During the course of process safety investigations, the heat of reaction is applied to calculate the so-called adiabatic temperature increase and subsequently the maximum temperature of the synthesis reaction (MTSR). The adiabatic temperature increase (ΔTad) is a function of the amount of the accumulated starting material, the reaction enthalpy, the amount of reaction mass and the specific heat of the reaction mass. It describes the theoretical increase of the reaction mass temperature, assuming that either part or all of the reaction is run adiabatically due to a cooling failure of the plant. In such a case, the temperature of the reactor content will increase proportionally to the conversion of the unreacted material. Consequently, the process temperature will increase by ΔTad reaching the MTSR.
Technology for Heat of Reaction
Ensure Safety-by-Design
For more than 30 years, the RC1 has been the gold standard in reaction calorimetry; RC1 is an instrument you can trust. The RC1mx builds on its predecessors by adding a level of convenience for faster development of better optimized, more robust, and economically viable processes.
- Understand Your Process
Determine thermodynamic data quickly and precisely under isothermal or non-isothermal conditions. - Heat Flow Calorimetry – Simply Reliable
Immune and robust against external influence, heat flow calorimetry allows to accurately and precisely measure the evolution of heat under process conditions. - Measure the True Heat of Reaction
Measuring the true heat of reaction is the basis to understanding the progress of chemical reactions, their kinetics and its hazard potential.
Thermal Conversion vs Chemical Conversion of a Reaction
The thermal conversion is relevant information for chemical process development, and describes the relationship between the partial heat of reaction as a function of time and the total heat of reaction. The calculation of the thermal conversion is based solely on the heat released during the reaction as opposed to the chemical conversion, which is based on the chemical conversion from reactants into products.
While the thermal conversion at the end of the reaction is always 100 %, the chemical conversion may be lower, and varies depending on the choice of process parameters. It is indeed the goal of chemical development to achieve the highest possible conversion of reactants, resulting in the highest yield possible.
Reaction calorimetry combined with real-time analysis, such as in-situ FTIR spectroscopy, is an ideal method to study the progress of a chemical reaction, the conversion of reactants, the formation of products, by-products and intermediates, while measuring thermodynamic information, such as the heat of reaction, the heat flow, the specific heat or the heat transfer at the same time.
Reaction Calorimetry Study Leads to Capital and Expense Savings
Thanks to information obtained from the RC1 (e.g. heat of reaction, heat capacity and the heat production rate), an established but challenging process was optimized and implemented at large scale within a very short time. The optimization resulted in savings of approximately $70,000 because no pilot stage was required. In addition, annual savings of $50,000 on production costs could be realized due to the less expensive equipment and the larger batch size.
Both steps of an indole synthesis, the phenylhydrazone synthesis followed by a Fischer ring closure, were investigated in an RC1 reaction calorimeter.
The main focus of the investigation was on the heat release rate, the heat of reaction and the heat transfer, as well as the impact of the reaction temperature, and at a later stage, the dosing rate on the information above. Based on the experimental data, the temperature and dosing regime, as well as the time and the cooling, performance required for the operations in the plant reactor could be estimated. The fact that the existing process could be modified to become virtually dosing-controlled also improved the safety at manufacturing scale, which substantially eliminated the need for expensive safety measures.
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Assure Efficient Mixing and Heat Transfer in Scale-up
Use Dynochem modeling to ensure effective mixing and heat transfer when scaling-up reactions. Dynochem makes it easy to quickly compare lab, pilot and production scale reactors, and find the appropriate mixing parameters to safely speed reactor-to-reactor process transfer. With data provided by reaction calorimetry and Dynochem modeling, quickly ensure chemical process safety and process performance across scales.
Publications
Heat of Reaction in Industry-Related Publications
Below is a selection of publications that discuss the heat of reaction or reaction enthalpy.
- Agosti, A., Bertolini, G., Bruno, G., Lautz, C., Glarner, T., & Deichtmann, W. (2017). Handling Hydrogen Peroxide Oxidations on a Large Scale: Synthesis of 5-Bromo-2-nitropyridine. Organic Process Research & Development, 21(3), 451–459. https://doi.org/10.1021/acs.oprd.6b00433
- Changi, S. M., & Wong, S. W. (2016). Kinetics Model for Designing Grignard Reactions in Batch or Flow Operations. Organic Process Research & Development, 20(2), 525–539. https://doi.org/10.1021/acs.oprd.5b00281
- Glotz, G., Knoechel, D. J., Podmore, P., Gruber-Woelfler, H., & Kappe, C. O. (2017). Reaction Calorimetry in Microreactor Environments—Measuring Heat of Reaction by Isothermal Heat Flux Calorimetry. Organic Process Research & Development, 21(5), 763–770. https://doi.org/10.1021/acs.oprd.7b00092
- Lakshminarasimhan, T. (2014). Predicting 24 and 8 h Adiabatic Decomposition Temperature for Low Temperature Reactions by Kinetic Fitting of Nonisothermal Heat Data from Reaction Calorimeter (RC1e). Organic Process Research & Development, 18(2), 315–320. https://doi.org/10.1021/op400301f
- Mitchell, C. W., Strawser, J. D., Gottlieb, A., Millonig, M. H., Hicks, F. A., & Papageorgiou, C. D. (2014). Development of a Modeling-Based Strategy for the Safe and Effective Scale-up of Highly Energetic Hydrogenation Reactions. Organic Process Research & Development, 18(12), 1828–1835. https://doi.org/10.1021/op500207r
- Wang, J., Huang, Y., Wilhite, B. A., Papadaki, M., & Mannan, M. S. (2018). Toward the Identification of Intensified Reaction Conditions Using Response Surface Methodology: A Case Study on 3-Methylpyridine N-Oxide Synthesis. Industrial & Engineering Chemistry Research, 58(15), 6093–6104. https://doi.org/10.1021/acs.iecr.8b03773
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