Predicting 24 and 8 h Adiabatic Decomposition Temperature for Low

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Predicting 24 and 8 h Adiabatic Decomposition Temperature for Low Temperature Reactions by Kinetic Fitting of Nonisothermal Heat Data from Reaction Calorimeter (RC1e) Thirumalai Lakshminarasimhan* Early Phase Chemical Development, Biocon Bristol-Myers Squibb R&D Center, Biocon Park, Bommasandra IV, Jigani Link Road, Bangalore-560099, India ABSTRACT: A new approach to determine the adiabatic decomposition temperature in 24 or 8 h (ADT 24/ADT 8) using a combination of nonisothermal heat data and kinetic modeling for the low temperature decomposition of a lithiated halogenated aromatic intermediate via the formation of a highly unstable benzyne intermediate is presented here. First order rate equations for the two steps were used for fitting the experimental heat curve generated from the temperature ramp of the lithiated reaction mass in RC1e. A good fit of experimental and predicted heat generation curves was obtained by fitting the kinetic parameters in DynoChem software using the heat data generated from the non-isothermal run in RC1e. The decomposition of a lithiated intermediate to a benzyne intermediate is a slow reaction and is sensitive to temperature, with rate constant (k) and activation energy (Ea) of 4.08 × 10−8 1/s (reference temperature Tref = −67 °C) and 99 kJ/mol, respectively. The decomposition of benzyne is a fast reaction and insensitive to temperature, with rate constant (k) and activation energy (Ea) of 1.34 × 10−3 1/s (Tref = −67 °C) and 2.3 kJ/mol, respectively. The kinetic parameters obtained from the fitting were then used to predict the ADT 24/ADT 8 and determine the maximum safe operating temperature for scale up. Kinetic studies indicate that dilution of the reaction with additional solvent has a minor impact on the predicted ADT 24 and ADT 8 and the decomposition is a strong function of temperature. Through this case-study, the methodology of using the heat curve from a single temperature ramp experiment in RC1e for fitting the low temperature decomposition kinetics and evaluating the criticality of the process step is demonstrated.

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calorimeter (ARC).1 Self-heating data obtained from a pseudoadiabatic calorimeter such as an advanced reaction system screening tool (ARSST) is also used to provide a quick conservative estimate of the adiabatic decomposition temperature (ADT 24/ADT 8) at which TMRad is 24 or 8 h.2 A series of isothermal experiments performed at different temperatures in a differential scanning calorimeter (DSC) can also be used by hazard evaluation laboratories in batch processing industries to obtain TMRad.3 Recently, AKTS software using isoconversional methods is also being used to predict the ADT 24/8 from the heat data obtained from dynamic DSC runs.4 Based on the adiabatic temperature rise of the main synthesis reaction, and ADT 24 for the possible decomposition reactions predicted using the data from the adiabatic calorimeter or DSC, it is possible to classify the thermal hazard of the reaction step using the Stoessel criticality index.3,5 However, in the case of low temperature reactions (carried out at −50 °C or less), an estimation of ADT 24/ADT 8 using this approach is limited by the lower end of the operating temperature range of most calorimeters. Even with an adiabatic calorimeter equipped with cryogenic capability, it will still be problematic to transfer air and moisture sensitive reaction mixtures from the preparing reactor to the test cell. Hence, a new approach to estimate ADT 24/ADT 8 for low temperature reactions is required. The use of nonisothermal heat data for kinetic fitting was demonstrated by Hoffman for the Diels−Alder reaction of isoprene and

INTRODUCTION One of the key elements for process safety testing in the pharmaceutical industry is to estimate the maximum safe operating temperature of exothermic reactions with decomposition potential during scale up. The thermal risk assessment of the reaction requires the evaluation of both the severity of the desired reaction and the probability of triggering secondary decomposition reactions. The severity of the desired reaction is evaluated by determining the adiabatic temperature rise using heat data from a reaction calorimeter. In the classical approach, the maximum operating temperature for reactions is based on a rule-of-thumb approach, wherein the reactions are carried out at X °C (typically 50−100 °C) below the onset of the decomposition temperature (Tonset). Furthermore, Tonset as determined experimentally depends on the sensitivity of the instrument and the scanning rate used. In several instances, this approach is restrictive and sets unrealistically low maximum operating temperatures. Hence, a realistic assessment of thermal stability should be based on the time scale of the runaway reaction. The probability of triggering secondary decomposition reactions is considered low if the temperature at which the time to maximum rate under adiabatic conditions (TMRad) is 24 h. This is the temperature at which the reaction mass has acceptable thermal stability. The kinetic approach based on TMRad is not arbitrary and is less dependent on the sensitivity of the instrument than the rule-of-thumb approach (vide supra). TMRad as a function of temperature can be determined by kinetic analysis of self-heating data generated from adiabatic calorimeters such as an accelerated rate © 2014 American Chemical Society

Received: October 23, 2013 Published: January 10, 2014 315

dx.doi.org/10.1021/op400301f | Org. Process Res. Dev. 2014, 18, 315−320

Organic Process Research & Development

Article

maleic anhydride.6 We envisioned that the nonisothermal heat data from a single temperature ramp experiment in the RC1e could also be used to fit the kinetic parameters in DynoChem, thereby allowing us to predict ADT 24/ADT 8 and define the maximum safe operating temperature during scale up.

Table 1. Parameters Used for Kinetic Fitting in DynoChem Software

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RESULTS AND DISCUSSION We had an opportunity to test this approach during our work on the synthesis of tert-butyl-(4-chloro-3-fluoro-2-iodophenyl)-

reaction

Tref (°C)

order

2 → 4 + LiF 4 → 5 (unknown)

−67 −67

1 1

solution of iodine (3.6 equiv) in THF to furnish 3 upon workup (Scheme 1). The main safety concern in the synthesis of 3 was the stability of intermediate 2. It is well-documented in the literature that o-lithiated halogenated aromatic compounds can present a significant thermal hazard, due to their propensity to form unstable benzyne intermediates (such as 4). We recognized that any increase in reaction mass temperature (e.g., due to fast addition of n-butyllithium or cooling failures during scale up) could lead to significant build up of benzyne intermediate 4, thereby compromising the thermal safety of the process.7,8 Therefore, it was important to understand the stability of 2 in order to define the maximum safe operating temperature for scale up. We initially planned to study the stability of intermediate 2 in the RC1e by gradually ramping the temperature of the lithiated reaction mass from low temperature (−67 °C) to near ambient conditions (20 °C).8 In this experiment, a 2 M solution of nBuLi in hexanes (3.5 equiv) was slowly added through an addition funnel to a solution of 1 (7 g; 28.5 mmol) in THF (120 mL), maintaining the temperature below −60 °C.9 The mass was held for a period of 1 h at −67 °C, and the heat of the reaction was found to be −397.3 kJ/mol (11.32 kJ for the 7 g batch) with an adiabatic temperature rise of 44.8 °C.10 Almost all of the heat was evolved during the addition, and the reaction could be controlled by dosing. After the addition of butyl lithium, the reaction mass temperature was gradually ramped

Scheme 1

carbamate (3). The first step in the formation of 3 involved the addition of 3.5 equiv of n-BuLi (2 M in hexanes) to a solution of 1 in THF (10−12 mL/g of 1) at −75 to −70 °C to provide the o-lithiated intermediate 2. The reaction mixture was held at −75 to −70 °C for a period of 1 h and was treated with a

Figure 1. Decomposition of o-lithiated intermediate 2 in RC1e. 316



Article

Figure 2. Fitting of qr data with integral limit from −58 to 20 °C.

(heating rate: 1 °C/min) to 20 °C from −67 °C. As expected, the onset of a significant exotherm was observed around −58 °C, reaching a peak heat rate of 113.4 W/kg at −16 °C (Figure 1). The heat data starting from −58 °C until the completion of the exotherm at 20 °C was used for obtaining the heat of reaction rather than −67 °C, which is the set temperature before the commencement of the temperature ramp. The heat of reaction was measured to be −626.5 kJ/mol (17.9 kJ for the 7 g batch), and the adiabatic temperature rise was calculated to be 71 °C (reaction mass: 157.8 g and Cp = 1.6 J/g.K).11 Extracting Kinetic Information from Heat Data. The relationship between heat data and reaction rate can be used to extract kinetic information.12 Heat evolution rate (qr) is directly proportional to the reaction rate (rA) and the volume of the reaction (Vrxn), with the proportionality constant being the heat of reaction (ΔHrxn). For any first order irreversible reaction A → P, the relation between qr and rA is given by eq 1.

Table 2. Fitted Kinetic Parameters from Dynochem parameter

value

confidence intervals (%)

unit

k1 k2 Ea1 Ea2 ΔHr1 ΔHr2

4.08 × 10−8 1.34 × 10−3 99 2.35 −293.4 −335.1

±4.7 ±48.3 ±0.6 ±155.4 ±8 ±7.2

1/S 1/S kJ/mol kJ/mol kJ/mol kJ/mol

Table 3. ADT 24 and ADT 8 Values for the Decomposition of Lithiated Reaction Mass lithiated intermediate mass with 17 mL of THF/g of 1

lithiated intermediate mass with 12 mL of THF/g of 1

ADT 24 (°C)

ADT 8 (°C)

ADT 24 (°C)

ADT 8 (°C)

−56

−51.3

−57.3

−52.6

Figure 3. TMRad 24 h for the lithiated mass (12 mL of THF/g of 1) at −57.3 °C (ADT 24). 317



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Figure 4. Profile of benzyne formation and decomposition.

Figure 5. TMRad for the lithiated reaction mass (17 mL of THF/g of 1) at −51.3 °C (blue dotted curve) and −56 °C (red curve).

where dTr/dt is the rate of temperature rise of the reaction mass Traditionally, experiments were done at different temperatures to obtain the temperature dependence of the reaction rate constant, i.e., the activation energy (Ea) and the preexponential factor (k0), by plotting ln k vs 1/T, as shown in eq 2. Kinetic Fitting of Nonisothermal Heat Data from RC1e. In our study, the heat and temperature data from the 7 g (28.5 mmol) batch experiment in RC1e were exported to DynoChem and used for fitting the kinetic parameters. In this case, qr data corrected for baseline heat signal (qr − qb) was used for fitting the rate parameters. It is assumed that almost all of the tert-butyl(4-chloro-3-fluorophenyl) carbamate (1) is converted to the lithiated intermediate 2 in the lithiation step.13 The known two step decomposition of the lithiated intermediate through the formation of the benzyne intermediate was used for the kinetic fitting (Scheme 1; Table 1).8

qr = rA ΔHrxnVrxn qr = −kCA ΔHrxnVrxn ⎛E ⎞ where k = k 0 exp⎜ a ⎟ ⎝ RT ⎠

(1)

⎛ E ⎞1 ln k(T ) = ⎜ − a ⎟ + ln k 0 ⎝ R ⎠T

(2)

The heat generation rate (qr) is calculated by applying heat balance to the reacting system and is given by eq 3. The reactor content temperature (Tr) and temperature of the jacket (Tj) are measured by the RC1e system. The total heat transfer (UA) and specific heat capacity (Cp) are obtained by performing calibrations during the run. ⎛ dT ⎞ qr = UA(Tr − Tj) + mCp⎜ r ⎟ ⎝ dt ⎠

(3) 318



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g of 1. Based on the data in Table 3, it is evident that dilution of the reaction mass with additional solvent has a very minor impact on the ADT 24/8 values. Figure 3 shows the time required for the reaction mass at −57.3 °C to reach the maximum self-heating rate of 21 °C/min over a period of 24 h. The initial decomposition of 2 is slow at lower temperature, and reaction proceeds faster at higher temperatures. The decomposition of 4 is a fast reaction (Figure 4), and the reaction mass quickly reaches the end temperature (37.2 °C for mass containing 12 mL of THF/g of 1). The temperature of the reaction mass has a significant impact on the predicted TMRad (Figure 5). It is also important to evaluate the heat effects of the iodination reaction and know the heat accumulation at the end of iodine addition. In the case of cooling failure, the accumulated heat due to unconverted 2 could result in a significant amount of benzyne. Hence, in a separate RC1e experiment, the heat effects of o-lithiation of 1 (with 12 mL of THF/g of 1) and iodination of 2 were evaluated for a 10 g (40.7 mmol) batch of 1. The heat evolved during the olithiation was found to be −430.6 kJ/mol,17 and the adiabatic temperature rise was estimated to be 66.4 °C (reaction mass: 165 g and Cp = 1.6 J/g·K). The reaction was dosing controlled with almost all the heat (thermal conversion ≈99%) evolved during the addition. The heat evolved during the iodine addition was evaluated to be −1450 kJ/mol (with respect to 1), and the adiabatic temperature rise was calculated to be 162.1 °C (Reaction mass: 260 g and Cp = 1.4 J/g·K). The iodination reaction was fast and highly exothermic but was found to be dosing controlled, with almost all of the heat evolved during the addition (thermal conversion ≈99%). The maximum temperature of the synthesis reaction (MTSR), accounting only for the heat accumulation at the end of dosing, would be −65.4 °C (−67 °C (i.e., Tr) + 1% of 162.1 °C). Though the formation of intermediates 2 and 3 was exothermic, the heat evolved during the reaction could be controlled by controlling the rate of addition of the reagents. Hence, the heat released by the lithiation and iodination reactions does not pose a severe hazard, as long as there is a control over the addition. In the case of o-lithiation of 1, the MTSR accounting only for the heat accumulation at the end of addition would be ≈ −66.3 °C (Tr: −67 °C + 1% of 66.4 °C), which is lower than the ADT 24 value (−57.3 °C). In the event of cooling failure, the boiling point of the solvent THF could not be reached (MTSR < MTT18) and the decomposition reaction could not be triggered (MTSR < ADT 24) and this process step would fall into a Stoessel criticality class of 2, indicating low thermal risk.3,5

Based on the mechanistic understanding of the reaction and assuming the decomposition mechanism does not change with temperature, qr is given by eq 4 qr =

∑ ΔHrirV i rxn i

(4)

Dynochem measures the rate constant at the reference temperature, and rate constants at other temperatures are calculated based on eq 5.14 ⎛ E ⎛1 1 ⎞⎞ k(T ) = k ref exp⎜⎜ − a ⎜ − ⎟⎟⎟ Tref ⎠⎠ ⎝ R ⎝T

(5)

The general approach followed in Dynochem for isothermal experiments is to fit the rate constant, k, at the reference temperature and then fit Ea for other runs carried out at different temperatures. In nonisothermal experiments where the temperatures are accurately measured, it is possible to fit simultaneously both the rate constant k and activation energy Ea by using all the data points of the experiment.14 The Dynochem approach fits kref and Ea using a nonlinear leastsquares algorithm. This approach was used to fit the nonisothermal data, which otherwise would not be possible by the classical approach. As seen from Figure 2, a good fit of experimental and predicted heat data was obtained using the heat and temperature data from −58 °C until the completion of the exotherm at 20 °C. Both the formation of benzyne intermediate and the decomposition of the benzyne intermediate were determined to follow the first order kinetics as initially assumed in the model. The data from Table 2 indicates that the formation of the benzyne intermediate is a very slow reaction (rate constant k = 4.08 × 10−8 1/s measured at Tref = −67 °C) but very sensitive to temperature (Ea = 99 kJ/mol). The decomposition of benzyne to unknown products is a relatively fast reaction (k = 1.34 × 10−3 1/s measured at Tref = −67 °C) and insensitive to changes in temperature. Furthermore, based on the regression, it is seen that the reactions heats for the two rate equations were −293.4 and −335.1 kJ/mol, as per eq 4 for the benzyne formation and decomposition respectively, thereby contributing roughly equally to the overall observed heat of reaction. Predicting ADT 24 and ADT 8 for the Decomposition of the Lithiated Intermediate 2. The fitted rate parameters were used to determine the temperature (ADT 24/ADT 8) at which TMRad is 24 h/8 h by using the optimization module in DynoChem. In order to determine the ADT 24/ADT 8 in the optimization module, the objective was set to reach the maximum self-heating rate [max(dT/dt)] under adiabatic conditions over a period of 24 or 8 h by selecting the temperature as the varying parameter in the software. The selfheating rate (dT/dt) of the reaction is given by eq 6. UA(Tr − Tj) q dT = r − dt mCp mCp

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SUMMARY AND CONCLUSION We have demonstrated that nonisothermal heat data from a single experiment in a reaction calorimeter can be used to fit the kinetics of low temperature reactions and predict the ADT 24 and ADT 8. A good fit of experimental and predicted heat data was obtained by adjusting the integral limits of the heat data in the temperature ramp. After estimating the adiabatic temperature rise of the main synthetic reaction and predicting the ADT 24 for the secondary reaction by kinetic fitting of the nonisothermal heat data, the criticality of the process was evaluated. The main advantage of this approach was that the heat and kinetic data of the desired reaction and the secondary decomposition reaction were determined from a single experiment. The entire safety evaluation experiment was carried out in the RC1e, obviating the need for transferring

(6)

Heat transfer terms were not included in the model in order to simulate the temperature and self-heating profile of the decomposition reaction under adiabatic conditions. Alternatively, dT/dt could be obtained by defining U = 0 for the jacket in the model (eq 6) and thus simulating the adiabatic condition.15,16 This approach was used to determine ADT 24 and ADT 8 values for a solution of 2 in 12 and 17 mL of THF/ 319



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(16) Hoffmann, W. Use of Models to Enhance Process Understanding. In Process Understanding for Scale-Up and Manufacture of Active Ingredients; Houson, I., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2011; pp 127−153. (17) The heat evolved during the o-lithiation in this experiment in the RC1e (−430.6 kJ/mol) is slightly higher than that in the first experiment (−397.3 kJ/mol). This may be attributed to the formation of a benzyne intermediate as result of temperature excursions during the course of uncontrolled addition of n-BuLi in this experiment. (18) In an open system, the maximum temperature for technical reasons (MTT) is the boiling point of the reaction system.

the reaction mixture into a separate test cell, thereby avoiding any inadvertent variation in the temperature of the reaction mixture. This technique is particularly useful for cryogenic conditions, as current approaches using ARC or DSC are often very difficult to carry out at subambient temperatures. This approach was employed to study an o-lithiation reaction at low temperature, and the process was successfully scaled up to 10 kg batch size.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The author thanks Manjunath Gujjar and Sabuj Mukherjee of BBRC for providing insight into the chemistry of the process. Simon Leung provided valuable guidance, and the author sincerely thanks him for his suggestions and fruitful discussions during the course of this work. Wilfried Hoffmann’s (Dynochem support team) input into the kinetic fitting of heat data is gratefully acknowledged. The author thanks Srinivas Tummala, Rajappa Vaidyanathan, Sridhar Desikan, and Jean Tom for helpful suggestions during the preparation of this manuscript.

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REFERENCES

(1) Townsend, D. I.; Tou, J. C. Thermochim. Acta 1980, 37, 1−30. (2) Theis, A. E.; Burelbach, J. P.; Askonas, C. F. Process Saf. Prog. 2009, 28, 135−140. (3) Stoessel, F. Thermal Safety of Chemical Processes; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2008. (4) www.akts.com. (5) Stoessel, F.; Fierz, H.; Lerena, P.; Kille, G. Org. Process Res. Dev. 1997, 1, 428−434. (6) Hoffmann, W.; Kang, Y.; Mitchell, J. C.; Snowden, M. J. Org. Process Res. Dev. 2007, 11, 25−29. (7) Hickey, R. M.; Allwein, S. P.; Nelson, T. D.; Kress, M. H.; Sudah, O. S.; Moment, A. J.; Rodgers, S. D; Kaba, M.; Fernandez, P. Org. Process Res. Dev. 2005, 9, 764−767. (8) Rawalpally, T.; Ji, Y.; Shankar, A.; Allen, J.; Jiang, Y.; Cleary, T. P.; Pierce, M. E. Org. Process Res. Dev. 2008, 12, 1293−1298. (9) The experiment was carried out at a higher dilution (17 mL of THF per g of 1) than the process recipe (10−12 mL of THF per g of 1). It was envisioned that the higher volume of solvent could better absorb any severe exotherm that could result from the decomposition of 2. (10) ΔTad = ΔH/mCp. Total energy released (ΔH) = 11.32 kJ. Reaction mass (m): 157.8 g. Specific heat capacity of the reaction mass (Cp) = 1.6 J/g·K. ΔTad = (11.32 kJ × 1000)/(157.8 g × 1.6 J/g·K) = 44.8 °C. (11) The total heat transfer (UA) and specific heat capacity (Cp) were measured by calibration before and after the temperature ramp, and linear variation of these values with respect to the temperature was chosen in the Mettler software. As the reaction mass was heated by 87 °C during the ramping, baseline proportional to temperature was selected to integrate the heat data in the Mettler software. (12) Landau, R. N. Thermochim. Acta 1996, 289, 101−126. (13) Analysis of the reaction mass after iodination showed 6% of 1 (by HPLC area). This is presumably due to adventitious moisture. (14) An approach for fitting the temperature dependence of the reaction kinetics can be found at: http://dcresources.scale-up.com. (15) Hoffmann, W. The Impact of Process SafetyWhat If Scenarios; Webinar training (Module 9); http://dcresources.scale-up.com. 320


Predicting 24 and 8 h Adiabatic Decomposition Temperature for Low

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