Chapter 8Calorimetric Methods of InvestigatingOrganic Reactions
U. Fischer and K. Hungerbuhler
In the pharmaceutical and fine chemical industries, process development and optimisationstart when the target chemical structure and a possible synthetic path have been identifiedby chemical research. Chemical process development ends when the production has beensuccessfully implemented in the final production facility.At the core of every chemical process there is an intended reaction generally accompanied
by unwanted side reactions. The intended reaction may proceed in one single step or, moreoften, takes place in several chemical transformations. Also, side reactions may proceed inmultiple steps thus leading to complex reaction schemes. Process development and processcontrol aimatchoosingoperatingconditions favouring the synthesisof themainproductandminimising unwanted by-products. A high yield signifies not only a higher economic profitfromproduct sales but also an efficient use of rawmaterials, energy (e.g. less energy requiredfor separations), and utilities, as well as the generation of less waste and lower emissions.These last mentioned advantages also improve the profitability of a process because smalleramounts of rawmaterials and less energy have to be paid for, and less waste has to be treatedand disposed of.Many tasks of process development and optimisation can be carried out, or are signifi-
cantly supported, only if a reaction model and the corresponding parameters are available.However, the reliability and usefulness of the data calculated strongly depend on the chosenreactionmodel and the quality of the reaction parameters used. A fundamental understand-ing of the thermokinetics is also a prerequisite for an investigation of process safety.Of course, most of the chemical reactions employed in the production of fine chemicals
and pharmaceuticals are rather complex from a mechanistic point of view. However, itshould be possible to propose reasonable empirical models for most of the reactions frombasic chemical knowledge. An empirical reaction model has to fulfil the needs of the earlyprocess development, but does not have to represent deep insight into the actual reactionmechanism. Thus, an empirical reactionmodel need only describe themost importantmainand side reactions with as few reaction parameters as possible. This will minimise the effortneeded to quantify the proposed parameters and increase the robustness of the model inthe later application.
The Investigation of Organic Reactions and Their MechanismsEdited by Howard Maskill
Copyright 2006 by Blackwell Publishing Ltd
Calorimetric Methods of Investigating Organic Reactions 199
As mentioned, all reaction models will include initially unknown reaction parameterssuch as reaction orders, rate constants, activation energies, phase change rate constants,diffusion coefficients and reaction enthalpies. Unfortunately, it is a fact that there is hardlyany knowledge about these kinetic and thermodynamic parameters for a large majority ofreactions in the production of fine chemicals and pharmaceuticals; this impedes the use ofmodel-basedoptimisation tools for individual reaction steps, so the identificationof optimaland safe reaction conditions, for example, can be difficult.Although many different analytical techniques have been developed during the past
decades, and variousmathematical algorithms exist to extract the desired information fromexperimental data, these methods nevertheless suffer from some fundamental drawbacks.For example, many analytical techniques requiring calibration and sampling still take toolong; with regard to sampling, therefore, online analytical techniques offer an importantadvantage. Furthermore, not all of the desired reaction parameters can bemeasured directlyand some can only be obtained by complex processing of the basic measurement data. Suchdeterminations are often time consuming or require sophisticatedmathematical techniques.In the early stages of process development, there might also be insufficient quantities of theessential test compounds available to carry out the required analyses. These facts call for afurther development of the available analytical techniques, or the invention of new ones.Otherwise, considerable potential for the improvement of many chemical processes, whichin fact needs to be achieved, might remain elusive.
8.2 Investigation of reaction kinetics and mechanisms usingcalorimetry and infrared spectroscopy
The kinetic and thermodynamic characterisation of chemical reactions is a crucial task in thecontext of thermal process safety as well as process development, and involves consideringobjectives as diverse as profit and environmental impact. As most chemical and physicalprocesses are accompanied by heat effects, calorimetry represents a unique technique togather information about both aspects, thermodynamics and kinetics. As the heat-flow rateduring a chemical reaction is proportional to the rate of conversion (expressed in mol s1),calorimetry represents a differential kinetic analysis method . For a simple reaction, thiscan be expressed in terms of the mathematical relationship in Equation 8.1:
qreact(t) r (t)Vr, (8.1)
where qreact is the reaction heat-flow rate (with units W) measured by a calorimeter, r is therate of reaction (mol m3 s1) and Vr is the reaction volume (m3). All three variables (qreact,r and Vr) are functions of time and the progress of the chemical reaction, and thus changeduring the investigation of the reaction. For complex reactions, the reaction heat-flow rateis influenced by the different reaction steps, and its allocation to individual steps might bedifficult.In contrast to calorimetry, most of the analytical techniques that are applied to the study
of kinetics, such as concentrationmeasurements or onlinemeasurement of reaction spectra(e.g. UVvis, near infrared, mid infrared and Raman), can be related to integral kinetic
200 The Investigation of Organic Reactions and Their Mechanisms
analysis methods . This can be expressed in terms of the proportionality in Equation 8.2:
si (t) ci (t), (8.2)where si represents the value measured by one of the analytical sensors mentioned above,which corresponds to the i th component in the reaction system with the concentrationtime profile ci (t) (expressed in mol m3). From this, it becomes clear that any combinationof a differential analysis method, such as calorimetry, with an integral analysis methodcould lead to a significant improvement in the kinetic analysis. Here, infrared spectroscopy,in particular attenuated total reflectance infrared spectroscopy (IR-ATR), will be discussed inmore detail. Comparedwith calorimetry, this analyticalmethod providesmore informationabout individual reaction steps and possible intermediates.
8.2.1 Fundamentals of reaction calorimetry
For the determination of reaction parameters, as well as for the assessment of thermal safety,several thermokinetic methods have been developed such as differential scanning calorime-try (DSC), differential thermal analysis (DTA), accelerating rate calorimetry (ARC) andreaction calorimetry. Here, the discussion will be restricted to reaction calorimeters whichresemble the later production-scale reactors of the corresponding industrial processes (batchor semi-batch reactors). We shall not discuss thermal analysis devices such as DSC or othermicro-calorimetric devices which differ significantly from the production-scale reactor.Calorimetric applications can also be differentiated by the way in which the reaction
temperature is controlled, i.e. isothermal, adiabatic, temperature programmed and isoperi-bole (constant coolant temperature) modes exist. For the purpose of scale-up, as well asfor kinetic and thermodynamic analysis of a desired synthetic reaction, isothermal reactionmeasurements are mostly preferred. This mode is supposed to be the easiest in applicationbecause no heat accumulation by the reactor content has to be considered, so no heat ca-pacities as a function of temperature are required. Therefore, we will focus on isothermalreaction calorimetric measurements. However, it should be mentioned that mainly non-isothermal measurements are carried out, especially in the field of safety analysis, in orderto investigate undesired decomposition reactions. Since non-isothermal experiments pro-vide information about the temperature dependence of the chemical reaction system underinvestigation, their information content is obviously larger, comparedwith isothermalmea-surements. This may be an advantage when sophisticated evaluation methods are available,but (especially for complex reaction systems) the information density of non-isothermalreaction measurements is often too large for the common analysis methods. In addition,isothermal conditions have the advantage that the temperature dependences of any sig-nals obtained from additional integral analytical sensors, which may be combined with thecalorimetric measurements, do not need to be considered.
8.2.2 Types of reaction calorimeters
Most of the existing reaction calorimeters consist of a reaction vessel and a surroundingjacket with a circulating fluid that transports the heat away from the reactor (see Fig. 8.1)
Calorimetric Methods of Investigating Organic Reactions 201
Cooling liquidCalibration / compensation
Fig. 8.1 Standard set-up of a reaction calorimeter . Left side: heat-flow, heat-balance and power-compensation calorimeters. Right side: Peltier calorimeters.
. Such devices can be classified according to their measurement and control principlesas follows.
188.8.131.52 Heat-flow calorimeters
The temperature of the reactor content (Tr, see Fig. 8.1) is controlled by varying the tem-perature of the cooling liquid (Tj ). The heat-flow rate from the reactor content through thewall into the cooling liquid (qFlow) is determined by measuring the temperature differencebetween the reactor content and the cooling liquid. In order to convert this temperaturesignal into a heat-flow signal (usually expressed in W), a heat-transfer coefficient has tobe determined using a calibration heater. To allow a fast control of Tr, the flow rate of thecooling liquid through the jacket should be high. The heat-flow principle was developed byRegenass and co-workers , andmost of the commercially available reaction calorimeters,such as the RC1 fromMettler Toledo, the SysCalo devices from Systag and the Simular fromHEL, are based on this principle.
184.108.40.206 Power-compensation calorimeters
The temperature of the reactor content (Tr) is controlled by varying the power of a compen-sation heater inserted directly into the reactor content. As with an electrical heater, cooling isnot possible, so the compensationheater alwaysmaintains a constant temperature differencebetween the reactor jacket and the reactor content. Thus cooling is achieved by reducingthe power of the compensation heater. The heat-flow rate from the reactor content throughthe wall into the cooling liquid (qFlow) is typically not determined because the heat-flow rateof the reaction is directly visible in the power consumption of the compensation heater. Thetemperature of the cooling liquid (Tj) is maintained at a constant temperature by an exter-nal cryostat. The power-compensation principle was first implemented by Andersen and
202 The Investigation of Organic Reactions and Their Mechanisms
was further developed by several researchers . Recently, small-scale power-compensationcalorimeters have been developed [5, 6]. Commercial power-compensation calorimeters areAutoMate and Simular (combined with heat flow) from HEL.
220.127.116.11 Heat-balance calorimeters
The temperature of the reactor content (Tr) is controlled by varying the temperature of thecooling liquid (Tj). The heat-flow rate from the reactor content through the wall into thecooling liquid (qFlow) is determined by measuring the difference between the jacket inlet(Tj,IN) andoutlet (Tj,OUT) temperatures and themassflowof thecooling liquid.Togetherwiththe heat capacity of the cooling liquid, the heat-flow signal is directly determined withoutcalibration. The heat-balance principle was first implemented by Meeks ; commercialversions are the RM200 fromChemisens, the SysCalo 2000 Series from Systag and the ZM-1from Zeton Altamira (developed in collaboration with Moritz and co-workers ).
18.104.22.168 Peltier calorimeters
The temperature of the reactor content (Tr) is controlled by varying the power of thePeltier elements. In contrast to the heaters in power-compensation calorimeters, Peltierelements can be used for cooling and heating. The heat-flow rate from the reactor contentthrough the Peltier element into the cooling liquid (qFlow) is calculated on the basis of therequired electrical power and the measured temperature gradient over the Peltier elements.The temperature of the cooling liquid (Tj) is maintained at a constant temperature by anexternal cryostat. Becker designed the first calorimeter using Peltier elements , and asimilar one was described by Nilsson and co-workers . The latter is similar to the oneshown in Fig. 8.1 (right-hand side), but the whole reactor is immersed in a thermostat baththat replaces the reactor jacket. The reactor base consists of Peltier elements and the rest ofthe reactor wall is insulated; consequently, the main heat flow out of the reactor is throughthe Peltier elements. Nilssons design was the basis for the commercially available CPA200from Chemisens. However, in the CPA200, the heat flow through the reactor base is notcalculated from the power consumption of the Peltier elements but by a heat-flow sensorwhich is incorporated between the reactor base and the Peltier elements.
8.2.3 Steady-state isothermal heat-flow balance of a generaltype of reaction calorimeter
The only heat-flow rate discussed so far has been the heat flow through the reactor jacket(qFlow inFig. 8.1). For the general case of an isothermal reaction, themainheat-flowrates thathave to be considered in a reaction calorimeter are shown in Fig. 8.2 and will be discussednext. In this discussion, ideal isothermal control of the reaction temperature, Tr, will beassumed . Consequently, no heat accumulation terms of the reaction mixture and thereactor inserts are shown in Fig. 8.2. However, this underlying assumption does not holdfor all applications and apparatuses.
Calorimetric Methods of Investigating Organic Reactions 203
Outer heat-flow balance
Inner heat-flow balance
Fig. 8.2 Main heat-flow rates that have to be considered in heat-flow, heat-balance and power-compensation reaction calorimeters running under strictly isothermal conditions . The heat-flow ratesinside a Peltier calorimeter are ana...