A New Paradigm in Oxidative Cleavage Reaction - American

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Chapter 13

A New Paradigm in Oxidative Cleavage Reaction: The Use of Continuous Reactors To Enable Safe Scale Up of Ozonolysis Ayman Allian* AbbVie, Process Research and Development, 1401 Sheridan Road, North Chicago, Illinois 60064 *E-mail: [email protected]

The formation of carbonyl compounds via oxidative cleavage of alkenes is an important synthetic step in API production. Ozone is an excellent oxidizing agent to perform this synthesis and is more efficient and environmentally friendly to current oxidation protocols that employ toxic metals. However, the exothermicity of ozonolysis reaction along with the instability of the intermediate involved hinders its implementation at scale in batch mode. In this chapter, we demonstrate that carrying out ozonolysis in continuous mode successfully addresses these safety thermal hazard concerns.

Introduction Oxidative Cleavage Reactions The oxidative cleavage of alkenes to form carbonyl compounds, primarily ketones and aldehydes, is an important tool for the organic chemist in the synthesis of pharmaceutical, complex natural products and fine chemicals including flavor, skin care and fragrance materials (1–3). A plethora of reagents such as potassium permanganate (KMnO4) and sodium periodate (NaIO4), catalyzed by RuCl3 or OsO4, have been used successfully to accomplish this type of transformation. An example of this important reaction is the synthesis of nopinone 2 from β-pinene 1 (Scheme 1). β-Pinene 1 is an abundant monoterpene natural product that is obtained by extraction of several plants and it is also a byproduct from the pulp

© 2014 American Chemical Society In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


and paper industry. The oxidation product, nopinone 2, is an important building block used in the synthesis of pharmaceutical products (4) and chiral ligands (5).

Scheme 1. Synthesis of nopinone 2 from β-pinene 1.

Several oxidants can promote the cleavage of β-pinene 1 (3). For example, high yields (95%) have been obtained using a combination of 4 equiv. NaIO4 with a catalytic amount of KMnO4 (20 mol%) (6). In other studies, a combination of NaIO4 with either OsO4 (7) or RuCl3 (8) also furnished reasonable yields of nopinone [2]. The latter metal-catalyzed oxidations accomplished the desired reaction, however, the presence of trace metal in the final product is intolerable in the highly regulated cosmetic and pharmaceutical industries. Therefore, the use of metal based oxidants usually requires exhaustive post reaction purifications and expensive analytical examination to assure the absence of metals to ppm levels. Even after metal extraction from the product, these isolated highly toxic metals present a disposal challenge. The need for a non-catalytic oxidant prompted our interest in another class of oxidant, namely ozone gas. Indeed, the use ozone as an oxidant, a process referred to as ozonolysis, has been successfully utilized to prepare nopinone from β-pinene (9). Historically at our research facilities, ozonolysis has been routinely practiced for small scale deliveries (-50 °C, the primary ozonide cleaves to form an aldehyde and carbony1oxide 4 which recombine to form the more stable secondary ozonide 5. The formation of hydroperoxides 6, especially in protic solvents, such as methanol, cannot be ruled out. Indeed, aqueous or polar systems are the preferred solvents for ozonolysis as they promote the decomposition of the formed ozonide to the less energetic hydroperoxides species. Finally, the secondary ozonide can 356 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


be further manipulated to form the desired products, either through oxidation to form carboxylic acids or by reduction to afford ketones, aldehydes or alcohols.

Scheme 2. General Reaction Mechanism of Alkene Ozonolysis The ozonides 3 and hydroperoxide 6 are of particular interest because they are extremely unstable and can create potential explosion hazards especially when present at high concentrations. Indeed, a safety evaluation (20) of the β-pinene ozonide reaction mixture (Scheme 1) showed a severe and fast self-decomposition with an onset temperature 48 °C. In another safety evaluation of the ozonolysis of a terminal alkene substrate similar to β-pinene 1, the DSC of an ozonized reaction mixture of tertiary allylic alcohol 7 to form hydroperoxide 8 by Ragan and co-workers (Scheme 3) showed an exothermic event at 45 °C (18). In order to ensure safety well below this relatively low temperature dictates that ozonolysis be conducted at a cryogenic temperature of ~ -60 °C in order to enforce a 100 °C safety margin (a common safety practice in the industry) between operating temperature and the onset temperature of a severe exothermic event.

Scheme 3. Ozonolysis of Allylic Alcohol 7

Ozonolysis Reaction and Quench Exothermicity During any ozonolysis, keeping the process temperature below the onset temperature of the decomposition of ozonide or hydroperoxide is critical. Besides heat losses to surroundings, maintaining these cryogenic temperatures is a challenging task due to the inherent exothermicity of ozonolysis. Consequently, quantitative understanding of the exothermicity becomes a matter of paramount 357 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


importance and it is typically experimentally obtained using calorimetric techniques such as Reaction Calorimetry (RC) or Accelerating Rate Calorimetry (ARC). However, there has been increased interest in using predictive techniques to estimate heats of reaction to corroborate experimental data and for obtaining an initial assessment of a synthetic route when experimental measurement is not feasible or practical (21). Indeed, Pfizers global process safety laboratories have adopted the use of heat of reaction estimation techniques especially in chemistries where predictive heat of reaction is in good agreement with the experimentally measured values (22). The most common techniques used to estimate the heat of reaction is simply to calculate the difference between heats of formation of the reactants and products, where heat of formation is estimated using Benson group increment theory (23). While the latter approach is fast and can be precise for smaller molecules, it suffers from potential inaccuracy largely due to the fact that the approach does not take into account ring strain as well as intermolecular and intramolecular interactions. At our research facilities, the use of density functional theory (DFT) computational chemical methods was utilized as a predictive tool for the heat of reaction. Obtaining the heat of reaction using theoretical chemistry aids in understanding the inherent heat of reaction. Experimental techniques, such as (RC), can be biased as it measure the sum of all heat generated during the reaction which encompass, beside enthalpy of reaction, heat generated by other phenomenon taking place during reaction such as crystallization and vaporization. The heat of ozonolysis reaction was evaluated using a CBS-QB3 (24) method implemented within Gaussian 03. Isobutylene was used as a model compound for terminal alkenes i.e. similar to β-pinene 1 and tertiary allylic alcohol 7 substrates discussed earlier. Furthermore, isobutylene resembles the substrate of interest in our laboratory that will be discussed later. DFT was utilized to calculate the heat of reaction of the relevant kinetic steps (Scheme 2) namely the formation of the secondary ozonide and its subsequent quench to the desired product with dimethylsulfide as shown in Figure 1.

Figure 1. Calculation of Enthalpy of Reaction for Isobutylene Ozonolysis 358 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


The results from the current DFT analysis indicate that ozone addition to form the secondary ozonide is very exothermic with heat of reaction of -445 kJ/mol. The results are in excellent agreement with calculated energy for the reaction of ethylene with ozone where the heat of reaction to form the secondary ozonide was -427 kJ/mol (25). The latter results from computational chemistry are also in good agreement with the experimental calorimetric results from Pfizer (Scheme 3) where the measured heat of reaction of ozone addition was 535 kJ/mol (18). These predictions are also in good agreement with the calorimetric measurement of β-pinene ozonolysis (Scheme 1) where the heat of ozone addition is 499 kJ/mol (20). Both experimental and computational methods show that ozone addition is very exothermic. In order to obtain a tangible sense of the consequences of the generated heat in the lab or at plant scale, the adiabatic temperature rise (ΔTad) associated with the exothermic event is calculated based on Equation 1. ΔTad reflects the theoretical temperature increase if generated heat is perfectly retained within the vessel. This is a useful value to determine since it gives a measure of the temperature rise of a reaction due to absence and/or loss of cooling.

where for every gram substrate, ΔHnet is heat evolved (in J), mtotal is total mass of reactor contents in (g), and Cp,r is the average heat capacity of the reactor contents (in J g-1K-1) (38). Utilizing the predicted heat of reaction calculated via DFT, the corresponding adiabatic temperature rise of the ozone addition to isobutylene reaction can be calculated using Equation 1 and was found to be 216 °C. In other words, if the energy of the reaction was released and the heat was not removed, the reaction mass could self-heat by 216 °C which reflect the intrinsic danger of running ozonolysis, even at cold temperatures. For example, if the reaction was carried out at the intended -60 °C, in the event of loss of cooling, the temperature can rise to 140 °C which is well beyond the onset temperature of ozonide/hydroperoxide decomposition. These temperatures are higher than the boiling points of the typical solvents used for ozonolysis and thus raises the potential for a catastrophic explosion. This exercise demonstrates the usefulness of using predictive methods, where a rapid understanding of the thermal severity of a reaction can be obtained before conducting the calorimetric experiments. It is worth mentioning that ozone addition is typically a dose-controlled reaction. Therefore, a slow addition of ozone, along with the deployment of appropriate engineering controls, can keep the temperature below the onset of decomposition of the oxygenated intermediate and thus mitigate the risk of a runaway reaction. For example, during the ozonolysis of tertiary allylic alcohol 7, charging ozone over 18 h, the team at Pfizer was able to maintain a temperature of -60 °C. Furthermore, the fact the reaction is dose-controlled also means that if the reactor temperature approached the decomposition onset temperature of the oxygenated intermediates, stopping the flow of ozone would immediately stall the reaction. This will be experimentally demonstrated in this study as a further layer of safety for our process. 359 In Managing Hazardous Reactions and Compounds in Process Chemistry; Pesti, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


DFT results also show (Figure 1) that the subsequent quench with DMS was also exothermic: 110 kJ/mol. DMS was used in our laboratory because of the ease of workup to remove its byproduct, DMSO, by simple water extraction. The heat generated by the quench corresponds to a 52 °C adiabatic temperature rise, which can again risk reaching the onset temperature of ozonide decomposition as the quench is conducted at 0 °C. It is worth mentioning that ozonide reduction rate via DMS is slow. Other more potent reducing agents have been used such as triphenylphosphine, trimethylphospine and thiourea (26). The latter reagents and their oxidized byproduct can be difficult to remove with aqueous washes. Recently, polymer-supported triphenylphosphine and thiourea were used where purification can be accomplished simply by filtration (27). Performing an Ozonolysis Reaction Traditional Batch Process Ozonolysis has traditionally been carried out in batch mode despite the challenges discussed in the previous section, namely its inherent exothermicity along with energetic intermediate formation. However, implementing the proper engineering controls can significantly reduce safety concerns. In a typical batch mode operation, the olefin starting material solution is added to the reactor and then cooled to cryogenic temperature (

A New Paradigm in Oxidative Cleavage Reaction - American

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