Scale-Up of Ozonolysis using Inherently Safer Technology in Continuous Flow under Pressure: Case Study on β-Pinene

Margaux Vaz, Daniel Courboin, Marc Winter, and Philippe M. C. Roth*

Article

Scale-Up of Ozonolysis using Inherently Safer Technology in

Continuous Flow under Pressure: Case Study on β‑Pinene

Cite This: Org. Process Res. Dev. 2021, 25, 1589 −1597

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sı Supporting Information

ABSTRACT: Despite its synthetic relevance, ozonolysis is still an underused reaction in the synthetic chemistry industries. This can

be attributed to safety issues while handling the ozone itself, alongside extra hazard related to unstable reaction intermediates. Flow

chemistry is inherently safer as it involves a small volume of reagent at any given time. Here, to address safety and technical issues,

we describe the design and testing of an ozone dosing line. A global risk assessment and the description of the setup, the analytics,

are presented in detail. This new dosing line enabled the successful scale-up of β-pinene ozonolysis in ﬂow, with a productivity of

over 16 g/h.

KEYWORDS: ﬂow chemistry, ozonolysis, scale-up, pressure, safety, risk assessment, process intensiﬁcation, pilot plant

4−26

INTRODUCTION

ﬂow

cally relevant targets.

In the academic ﬁeld, ﬂow ozonolysis research has been

including scale-up aspects, as well as pharmaceuti-

■

28−30

Ozone is an unstable and reactive gas with a high propensity to

vigorously decompose into oxygen with signiﬁcant energy

1−38

39−45

carried out in tubular systems,

microreactors,

release. The idea of harnessing its oxidative properties has

sometimes with a ﬁlm, or ﬁlm-shear reactors, usually at a

small scale (mmol). In the research dedicated toward

industrialization, safety requirements led to switching batch

to alternative ﬂow ozonolysis processes. This was applied in

the ivacaftor synthesis, in which the ozonolysis was switched

from batch to a series of continuous stirred tank reactors

long been present and applied in many ﬁelds such as food,

water treatment industry, and medical industry. In synthetic

chemistry, the ozonolysis reaction is widely used. Ozone is a

strong oxidant, reacting with unsaturated C−C bonds (among

other reactive groups) and delivering oxidized products

directly or with a tandem reaction, which inﬂuences itself

the formed ﬁnal product. This reaction is considered green due

to a couple of factors: the use of a clean reagent and the

(

CSTRs). The ozone concentration was kept low by a nitrogen

gas ﬂow, ca. 1000 times higher than the liquid one. To

synthesize the oncologically relevant AMG232, an ozonolysis−

Pinnick tandem transformation was carried out in a CSTR

absence of metals. However, despite syntheses up to

multikilogram scale in the pharmaceutical ﬁeld, ozonolysis

setup using 2 equivalents of ozone.

Increasing the

use remains limited for safety reasons (and the associated

0−12

productivity using a high ozone ﬂow rate (285 g/h) led to

high conversion but decreased the selectivity. The oxygen

concentration in the reactor was maintained below 5%,

mitigating safety hazards. Another ozonolysis reaction of an

API intermediate was developed at a kilogram scale under a

nitrogen ﬂow of 17 L/min, consuming a signiﬁcant amount of

cost).

Process intensiﬁcation in the ﬁeld is required and

is still in its infancy.

As ozone is a gas, working under pressure would allow

higher mass transfer and solubility, thus leading to a higher

reactivity. However, for safety reasons, the current reported

industrialized processes, to the best of our knowledge,

exclusively involve atmospheric pressure conditions or slightly

higher. Additionally, the voluntarily decreased reactivity of the

process and the costly safeguards may mitigate the ﬁnancial

viability of the processes. Hence, ozonolysis is underused

industrially compared to its synthetic eﬃciency. Lately, the

gas.

Using a loop reactor, successful ozonolysis of

chrysanthemic acid was scaled up to 0.5 t/day, highlighting a

successful setup design.

Alternatively, a homogeneous continuous ozonolysis has

been reported involving liquid ozone (3.7−4.3 mol %)

dissolved in a supercritical CO (70 bar, 0 °C) carrier, and

no attempt to scale up this process was disclosed.

need for a safer and scalable ozonolysis alternative has been

explicitly stated. For instance, while discussing the synthetic

route toward methyl glyoxaldehyde, ozonolysis is discussed by

the authors as an interesting option. “We expect that the rise of

Received: January 8, 2021

Published: July 2, 2021

continuous methodologies mitigates the hazard of ozone...”.

Flow chemistry appears as a viable alternative approach,

,18−22

both in terms of risk management

and environment

control as it involves a low reactive inventory. There has

been signiﬁcant interest in developing ozonolysis reactions in

2021 American Chemical Society

Organic Process Research & Development

Org. Process Res. Dev. 2021, 25, 1589−1597

589

Article

Figure 1. (a) Setup of the reaction system including the new dosing line and the reactor. For clariﬁcation purposes, the rinsing system (nitrogen/

acetone) is not included here. The complete setup can be found in Supporting Information. (b) Ozone dosing line. (c) Reaction setup.

The relative scarcity of the reported ﬂow process is likely the

result of health and safety concerns. Due to its toxic nature,

handling ozone inherently creates a danger. On top of hazards

linked to its accidental release, a major issue is the potential

accumulation of explosive ozonides in the reaction setup. Last

but not the least, management of the heat released during the

exothermic ozonolysis reactions (and its subsequent quenching

reaction) represents an additional challenge. The best way to

avoid issues with ozonides is to make sure they are quenched

continuously and do not accumulate neither in the reactor nor

in the collection tank.

throughput of ozone for the kilo lab scale, Corning G1

Reactor.

RESULTS AND DISCUSSION

■

Risk Management: General Aspects. Before running

experiments or even designing the line (Figure 1 a), “what if”

scenarios were envisioned (see Supporting Information). This

led to the risk management considerations detailed below.

Additionally, the following general actions were implemented

additional minor points are described in Supporting

Information ):

Hence multistep reactor possessing high mixing and heat

53,54

• Detailed procedures of the potential scenarios identiﬁed,

including required actions to restart the equipment and

process, were prepared beforehand.

transfer capabilities are generally used to perform this task.

Ozonolysis has been previously demonstrated in a Corning

reactor, albeit at a laboratory scale. However, while aiming at

increasing productivity, the limit of the current methods is low

ozone concentration and pressure. Building on the previous

work accumulated in the research ﬁeld, we endeavored to

develop a system which would explore the underdeveloped

area of ozonolysis reaction in ﬂow under pressure. As a target, a

kilo laboratory scale system able to deliver up to 10% wt ozone

and 10 bar pressure would considerably improve reaction

productivity and range of accessible conditions. We therefore

planned to design an ozone dosing line, compact and shielded,

incorporating control tools, and capable of delivering high

•

Easily accessible emergency buttons were set to trigger a

system shutdown (one for the ozone dosing line, one for

the other lines).

Risk Management: Ozone Exposure Level. Ozone is a

highly toxic species even at concentrations as low as 0.3 ppm.

The human olfactive detection threshold is 0.045 ppm, but the

sensitivity is unreliable as stronger smells or habituation can

prevent its detection. Ozone exposure has been assessed by the

Occupational Safety and Health Administration (OSHA),

with a time-weighted average (TWA) of 0.1 ppm and short-

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term exposure limit (STEL) of 0.3 ppm (i.e., the maximum

exposure level for a substance in an atmosphere in which

someone works for 15 min). Finally, its immediately dangerous

to life or health (IDLH) threshold is 5 ppm.

Based on these data, time estimation to reach threshold

levels are reported in Table 1, assuming continuous ozone

medium (pH, impurities, and UV irradiation) also impact the

ozone decomposition rate. Among key parameters, the heat

management is detailed in Supporting Information as it

prevents ozone thermal decomposition.

The pressure is likely to have an impact on the rate of

decomposition of ozone. The explosion properties of ozone/

oxygen media up to 20% vol and pressures up to 10 bar have

Table 1. Time Before the Ozone Concentration Reaches

Threatening Levels (in a Closed Environment)

been reported. The inﬂammability threshold for an ozone/

oxygen mixture has been reported at 13% vol (i.e., 19.7% wt)

at 10 bar (14% vol at atmospheric pressure). This limit

means that the mixture will spontaneously decompose under

these conditions at room temperature.

.1 ppm

0.3 ppm

(STEL) (s)

5 ppm

(IDLH)

(

TWA) (s)

laboratory 120 m³

3.92

0.1

11.7

0.2

3 min 15 s

4.9 s

To mitigate risks related to ozone-oxygen explosive auto

decomposition, the following measures were put in place to

align with literature conditions:

volume close to the

_o_p_e_r_a_t_o_r_:₃_m3

•

A maximum 10% wt ozone working concentration was

set.

release in the laboratory environment (under the maximum

working ozone concentration conditions, see Supporting

Information for calculation details). In the working space

close to the user, dangerous concentrations would be reached

within seconds. Therefore, an in-depth risk analysis was

performed.

•

Both the compressor and the ozone generator were

cooled down while monitoring the ozone temperature.

The compressor had an active cooling system.

A pressure relief valve (PRV), set at 12 bar, was included

at the outlet of the compressor. The outlet of the PRV

rejects the gas directly in the exhaust.

A 10 bar maximum working pressure was set, monitoring

with a sensor which would automatically shut down the

ozone dosing line in case of overpressure (11 bar). The

pressure in the reactor was induced using a back

pressure regulator (BPR), which could be easily adjusted

and released by operators. The actual setting varied

depending on the conditions and is reported in

Supporting Information (typically in the range of 8−9

bar).

•

To prevent ozone release, the following safeguard steps were

implemented:

•

The laboratory was equipped with an ozone detector,

next to the fume hood, constantly monitoring the

ambient air. Its 0.15 ppm threshold would trigger an

electrical laboratory shutdown. Each operator, while

handling equipment in the fume hood, carried a portable

ozone detector.

•

Reactions were carried out in a fume hood in which a

suction ﬂow rate of 1000 m /h was checked beforehand.

The air ﬂow rate was constantly monitored via an

independent system. Any exhaust failure would

automatically stop ozone generation and turn oﬀ the

oxygen feeding.

The ozone dosing line was designed within a casing

connected directly to an exhaust system (cf. Figure 1a−

c). Automatic pressure monitoring would prevent the

dosing line use without active air extraction.

The tubing between the dosing line and the reactor was

double-jacketed. The dosing line was designed to

minimize the internal gas, ensuring a minimal volume

of ozone/oxygen release in the event of a pipe

disconnection.

Use of an inline NMR monitoring system to check the

reaction completion, checking the consumption of ozone

Risk Management: Mixing Ozone/Oxygen with

Highly Flammable Solvent. Ozonolysis solvents tend to

be ﬂammable in air. Under pure oxygen and high pressure

conditions, this risk increases. The European Industrial Gases

Association (EIGA) reported that “the higher the oxygen

concentration and pressure... the ignition energy to promote

the combustion reaction is much lower, temperature of the

ﬂame is higher, and consequently, the destructive capability of

•

the ﬂame is greater”.

Hence, mixing ﬂammable solvent with oxygen under

pressure presents potential risks. The activation energy

triggering combustion is reduced in a pure oxygen atmosphere

compared to an air atmosphere by a factor of 50−200 (i.e., 2.6

μJ vs 1150 μJ for acetone, used in the present research, in pure

•

oxygen at atmospheric pressure).

(

via starting material conversion)

To mitigate this risk, the following actions were undertaken:

Handling Ozone−Oxygen Mix at High Pressure. In

addition to the toxicological risk itself, ozone is unstable by

nature and decomposes into oxygen while freeing energy

•

Use of “oxygen cleaned” (grease- and lubricant-free)

components in the ozone dosing line.

• Through the use of a continuous ﬂow reactor connected

to a liquid−gas separator at the outlet, the volume of the

solvent in contact with oxygen was minimized. The

separator was a stainless steel T-union with the gas

outlet going vertically upward, while the gravity pushed

down the liquid. A visual check was performed to make

sure the separator did not form too many aerosol

droplets: the low temperature and use of a nonsparking

and conducting material (stainless steel) minimized the

risk of static buildup. There was a maximum of 50 mL of

acetone volume in contact with oxygen in the reactor at

any time.

(

possibly via explosion). The rate of decomposition

depending on the temperature is presented herein (Table 2).

The literature slightly diverges on the exact values, but the

order of magnitude (i.e., hours at room temperature) appears

57,58

to be fairly consistent.

The conditions and nature of the

Table 2. Ozone Decomposition Rate Depending on the

Temperature

temperature

20 °C

100 °C

250 °C

decomposition rate

30% after 12 h

100% in 5 h

100% within 1 s

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•

Both the ozone dosing line and reactor were electrically

grounded to avoid static electricity buildup.

An electrically conducting liquid was used as a heat

exchange ﬂuid to prevent static electricity buildup inside

the reactor glass ﬂuidic modules (FMs).

Table 3. Ozone Dosing Line Speciﬁcations

maximum gas ﬂow rate (O + O )

2000 mLn/min

minimum gas ﬂow rate (O + O )

100 mLn/min

10% wt

maximum O concentration in O₂

O mass ﬂow rate

from 0.8 to 16.9 g/h

from 17.6 to 311 mmol/h

12 bar

•

Constant nitrogen ﬂow in the collection tank (to be

below the oxygen ﬂammability range).

O molar ﬂow rate

design pressure

Constant dilution of the gas phase outlet (max 120 Ln/

h) by the fume hood air ﬂow (1000 m /h).

At higher pressure, the gas solubility increases and more gas

molecules are present in the gas phase. This drives the reaction

forward through higher mass transfer.

Ozonide and Peroxide Management. Ozonolysis

reactions generate ozonides and other peroxide intermediates.

These species are highly unstable and potentially explosive.

Thus, the following risk mitigation steps were implemented:

Thus, the reactor pressure was set using a dome-loaded BPR

described in Supporting Information). These BPRs have been

(

internally tested to operate with a stream containing gas and

liquid. Three chillers allowed separate control and ﬂexibility

over the temperature of the system (although a single unit has

enough capacity to deal with the situation, see Supporting

Information).

•

Use of a quenching reagent: triphenylphosphine. An

excess of triphenylphosphine was used (3 equivalents) to

be sure of the absence of peroxides.

•

Frequent peroxide detection tests were performed in the

outlet solution (see Supporting Information).

One chiller was used for precooling and the second one was

used for the reaction, while the third one dealt with cooling of

the quenching reaction. A gas−liquid separator was installed at

the outlet, and a subsample of the liquid stream was sent

through NMR for analysis, while the main stream was

continuously collected in the outlet tank.

Setup Experiment and Ozone Dosing Line Design. In

line with the work performed in the risk analysis, the

experiment setup was designed as described in the Process

Flow Diagram (or PFD, Figure 1). This includes the ozone

dosing line design (Figure 1b) and the new equipment within

this experimental setup.

The use of inline NMR analysis greatly helped the project

see Supporting Information) by knowing when the steady

All the selected parts were screened upon their compatibility

(

2,63

with ozone.

Materialwise, the pieces selected for this work

state was reached. Indeed, quasi-instantaneous qualitative

results were obtained (the delay was due to the volume from

the outlet of the reactor to the NMR). On top of checking the

presence of the desired product, this setup gave an estimation

of the reaction conversion.

include stainless-steel 316 elements (valves, pressure relief

valves, check valve, compressor...), PFA piping, poly-

(

tetraﬂuoroethylene) (for gaskets and compressor parts), and

FKM gaskets for the pressure transmitter. For the reactor part

itself, the gaskets used were made of Perlast perﬂuoroelastomer

Checking the system had reached its steady state was

performed by verifying that the pressure remained constant

while the NMR conversions remained steady. Then, a sample

was collected (see Supporting Information) for oﬄine analysis.

Choice of Reaction. In order to perform continuous ﬂow

ozonolysis at the pilot scale (or kilo lab), a suitable chemical

reaction was selected. As implementation of ozonolysis in ﬂow

could be an asset in the pharmaceutical industry, a relevant

substrate was selected: β-pinene. It is a byproduct from the

(

FFKM) G75S and glass (for the reactor ﬂuidic modules). The

components from the reactor (gaskets) were also checked to

ensure a chemical compatibility with solvents and reagents

(

acetone,...). No leak was detected in the course of this

research project.

An eﬀective ﬂow rate controller (whose inner material is

ozone compatible, detailed in Supporting Information ), ozone

generator, and compressor were selected, to match both

process and space optimization requirements. A limited

footprint was indeed targeted to ensure that the dosing line

can be easily moved where required (close to a fume hood), in

a fairly constrained laboratory/pilot plant environment.

With its cart and reliable ﬂexible connection to the vents (air

pulp and paper industry. Upon ozonolysis, β-pinene turns

into nopinone, an important building block used in the

27,64−68

synthesis of pharmaceutical products (Scheme 1).

This

model reaction was identiﬁed to assess the scalability of the

system.

ﬂow rate of 150 m /h, i.e., 800 times higher than the ozone/

oxygen ﬂow rate), the ozone generator can operate outside the

fume hood (as it is directly linked to its separate exhaust

system). Safety interlock is managed through direct and simple

hardware design. Furthermore, the ﬂow rate control, the

regulation of the ozone generator, and data acquisition were

performed via a computer, enabling a straightforward user

interface.

Scheme 1. Ozonolysis of β-Pinene to Nopinone (after

Quench)

Once conceptualized, the new ozone line was built and

tested under real conditions. Its targeted speciﬁcations (Table

) met the discussed risk mitigation requirements.

The other experimental equipment (reactors, reagents tanks

Even though the carbon−carbon double-bond oxidative

cleavage of β-pinene has been reported, the industrial scale

application of the process relies on the reactivity of metal to

push forward the transformation. More speciﬁcally, it involves

precious metals or dangerous chemicals (NaIO with KMnO ,

and dosing line, and downstream equipment) were set up in a

fume hood. The reactant and quench solutions were metered

via two dosing lines including a gear pump and Coriolis mass

ﬂow meter. The reactor was a kilo lab reactor (G1), with 9

glass FMs. Not all of them were used for each experiment,

adding ﬂexibility to change the volume of the reactor.

NaIO with OsO , or NaIO with RuCl ). This not only

depletes natural resources but also leaves potentially toxic

metal traces in the solution. Additionally, the use of ozone

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Table 4. Results While Varying the Ozone Concentration

Reactor

residence

conversion of

yield of

productivity

ozone

Liquid

gas

entry C_β_‑_p_i_n_e_n_e(M) (% wt)

(mL/min) (mLn/min) ozone/β-pinene

(mL)

time (s)

β-pinene (%)

nopinone (%)

(g/h)

0.05

2.7

4.7

7.0

2.7

4.7

7.0

745

1117

295

0.57

1.5

0.57

1.5

0.57

100

2.5

4.1

4.9

3.9

6.4

6.3

3.22

5.58

6.85

512

768

100

1.5

All reactions were performed at 20 °C and 10 bar. Ozone weight concentration of the gaseous phase. Flow rate of the β-pinene solution inlet.

Gas ﬂow rate at the inlet of the reactor (normalized mL/min at ambient pressure). Stoichiometric ratio of ozone to β-pinene after conversion in

mol. Volume of the reactor based on the number of FM (each FM volume: 9 mL). Residence time calculated based on the volume of the reactor

and the actual ﬂow rate including liquid and gas, (see Supporting Information ). Ratio calculated according to the NMR signal. GC−MS

calculated using the external standard. Hourly nopinone productivity based on the yield, concentration, and the ﬂow rate.

limits the number of chemicals present in the solution, easing

the downstream process.

Reaction Optimization. An experimental plan was set up,

a variety of potential side products, some of which are acidic

(possibly formic acid). After ozonolysis, pH measurement of

solutions reproducibly indicated 5, pointing out the presence

of an acidic species. Among others, a sharp peak at 10 ppm in

inline NMR was observed, possibly due to acidic compound

traces, but not conﬁrmed by oﬄine analysis due to its high

volatility (boiling point 20 °C). This was in accordance with

using the model reaction previously studied by the Kappe

group, as a basis for scale-up experiments. Initially, the

conditions from the original paper (keeping a ratio to have β-

pinene in excess compared to ozone) were maintained, such as

the solvent (acetone), the residence time (11 s), the

temperature (20 °C), and the ratio of ozone to β-pinene

NMR spectra which displayed no major unknown species.

Second, the actual gas ﬂow rate is high compared to the

liquid ﬂow rate (typically Table 4, entry 4, the liquid ﬂow rate

is 30 mL/min compared to a total gas ﬂow rate of 1117 mLn/

min). There is a factor three in diﬀerence between the two

(real gas ﬂow rate under these conditions is 109 mL/min). As

the product has a boiling point of 209 °C, the hypothesis of it

being entrained to the gas phase by the evaporating acetone,

similar to air stripping (and therefore not being detected),

seems unlikely (but cannot entirely be ruled out). To

mitigate this drawback, a possible way forward would be to

work at higher concentration or cool the reaction outlet.

An alternative explanation can be drawn from another case.

In this reported example, the impact of the temperature on the

batch reaction yields of the Z-(+)-Abienol ozonolysis is

studied. In their case, they typically report that the process

occurring at cryogenic temperature (−60 °C) had a higher

yield (88%) than the reaction performed at room temperature

(51%). Although the methods, substrates, and setup are

diﬀerent, the impact of the temperature might be relevant and

avoid the destruction of the products.

Another batch reported β-pinene ozonolysis even under

cryogenic conditions where the actual yield (65%) is

signiﬁcantly lower than the starting material conversion

(

0.57).

A subsequent screen of conditions was planned to intensify

the process conditions, ozone stoichiometries of 1 and 1.5

were tested, and the dosing line capabilities were explored. All

the experiments were carried out under conditions for which

the gas behavior in the reactor has been characterized. The

pressure drop across the reactor is reported in Supporting

Information .

As reported in Table 4, entry 1, the initial conditions with

.57 equivalents of ozone led to a 56% conversion. Under

stoichiometric conditions, the conversion increased to 92%

(

entry 2), but an excess of ozone was required to reach 100%

entry 3). The liquid/gas mixing behavior does not seem to be

a limiting factor in this setup. This can be seen by quasi-

complete conversion when using a stoichiometric amount of

ozone (entry 2). The results from the initial screening were

encouraging as no unforeseen factors inﬂuenced the reaction

under these conditions.

Additionally, although the presence of dimers has been

reported, their presence or absence (unchecked in our case)

does not appear to signiﬁcantly impact the reaction. In our

case, a complete β-pinene consumption indicated a full ozone

depletion due to their 1:1 stoichiometric ratio, irrelevant of the

potential presence of dimers. Additionally, the dimer kinetic

formation would be hampered by the relatively short residence

time in the reactor (due to the high gas ﬂow rate).

7,72

(100%).

In their case, the solvent was involved in the

reaction. This still seems unlikely on our case.

After this initial set of experiments, other trials were run,

keeping the ozone concentration at 10% wt, while varying the

gas ﬂow rate to keep the same stoichiometric ratios (entries 7−

9). The aim was to ensure that the equipment could deliver

both a steady ﬂow rate and ozone concentration. Results show

similar conversions as before (entry 7 vs entries 1 and 4) which

demonstrates that we can work at high ozone concentrations.

Higher ozone stoichiometry is the main factor impacting the

conversion.

Adding more ﬂuidic modules allowed us to subsequently

increase the residence time, as well as the liquid and gas ﬂow

rates, to investigate the eﬀect of a higher ﬂow rate and better

mass transfer at the same ozone/β-pinene ratios as previously

described (entries 4 to 6). Slightly higher conversions were

observed compared to earlier ones (e.g., entry 1 vs 4).

Surprisingly, the calculated yields (by GC−MS) are

consistently signiﬁcantly lower than the conversion. Hypoth-

eses explaining this phenomenon were drawn. First, a

theoretical paper studying this reaction shows that it leads to

Based on previous results, attempts to increase the

productivity, by increasing reaction concentration, were carried

out (Table 5) with a 1 equivalent of ozone. The gas ﬂow rate

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Table 5. Tests Resulting in Higher Productivity

β‑pinene

(M)

Reactor

(mL)

residence

conversion of

yield of

productivity

ozone

(% wt)

Liquid

(mL/min)

gas

entry

(mLn/min) ozone/β-pinene

time (s)

β-pinene (%)

nopinone (%)

(g/h)

0.05

0.1

4.7

6.95

37.5

1862

100

10.4

11.1

16.2

All reactions were performed at 20 °C and 10 bar. Ozone weight concentration of the gaseous phase. Flow rate of the β-pinene solution inlet.

Gas ﬂow rate at the inlet of the reactor (normalized mL/min at ambient pressure). Stoichiometric ratio of ozone to β-pinene after conversion in

mol. Volume of the reactor based on the number of FM (each FM volume: 9 mL). Residence time calculated based on the volume of the reactor

and the actual ﬂow rate including the liquid and gas (see Supporting Information). Ratio calculated according to the NMR signal. GC−MS

calculated using the external standard. Hourly nopinone productivity based on the yield, concentration, and ﬂow rate.

was kept identical. As shown in entry 1, compared to Table 4, a

higher overall ﬂow rate led to complete conversion. This

highlights the excellent mixing between gas and liquid phases

in the reactor. Entries 2 and 3 were performed in doubling the

reagent concentration. The corresponding levels of conversion

are quasi-quantitative, showing that the mixing is eﬀective and

the kinetics is fast. Finally, productivities up to 16.2 g/h were

reached.

potential risks, scale-up to the industrial scale using similar

equipment with higher throughput can be envisioned.

CONCLUSIONS

■

A dosing line was successfully set up to perform safe and high

throughput continuous ﬂow ozonolysis reactions under

pressure. This new system is an improvement on current

methods while mitigating the inherent risks associated with the

process itself, as risk assessment was at its core since its

inception. Beneﬁtting from the advantages of the ﬂow process

Interestingly, the change in quenching conditions (com-

pared to the original study from Kappe et al.) repeatedly

resulted in the complete absence of peroxide traces in the

outlet stream. The change from a milder quench (water) to the

more potent triphenylphosphine was successful. However, the

implementation of the reaction at the industrial scale would

most likely require further optimization of such parameters to

avoid buildup of waste. This step would necessitate a speciﬁc

focus as any leftover untreated ozonide is a potential hazard.

The current set of experiments also beneﬁtted from the use

of inline NMR. Indeed, the ability to know when the steady

state was reached was paramount to optimizing the experiment

in a short duration and mitigating any safety hazards (related

to the presence of ozone or ozonides). The use of NMR

showed that once the ozone was sent into the reactor itself, the

steady state was reached quasi-instantaneously, as within

minutes, the ﬁnal conversion was shown by NMR. The only

latency was the time required for the outlet stream to reach the

NMR equipment. This result saves time and resources and

leads to more eﬀective experimental runs. Therefore, the use of

appropriate analytical equipment is even more critical in such

cases of hazardous chemistries.

(

safety and inline analysis), this new equipment was able to

eﬀectively scale up a benchmark ozonolysis from laboratory to

kilo lab scale. The productivity was increased up to 16 g/h.

Regarding the gas/liquid mixing capability, the high con-

versions indicate that, with a 1:1 ozone/β-pinene ratio, the

mixing capability and the size of the reactor were suﬃcient.

This dosing line can help researchers implement their

reactions at higher scale, by performing their reaction in a

controlled and safe way. We believe that this process

intensiﬁcation will be highly desirable in the current target

toward a more sustainable future.

EXPERIMENTAL SECTION

■

Safety Warning. Both ozone and peroxides species are

very dangerous, even at trace levels, and working under these

conditions requires a high level of protection including

appropriate personal protective equipment (and a risk

assessment).

General. All reactions were conducted at 20 °C and 10 bar.

All the reagents and solvents were used as received from

commercial sources without any additional puriﬁcation.

Procedure (Refer to Figure 1a). All chillers were

switched on and allowed time to reach their target temper-

ature. The ozone dosing line was started, and nitrogen was

used to ﬂush and then stabilize the system. The reagent and

quenching dosing lines (pump with its ﬁlter, ﬂowmeter) were

started, using a rinsing solvent. The inline NMR system was

warmed up (and its pump). At the outlet (collection tank), the

diluting nitrogen gas stream inlet was opened.

Scale-Up. The original report, which inspired this work,

had a nopinone productivity of 0.24 g/h. The current results

led to a maximum nopinone productivity of 16.2 g/h (Table 5,

entry 3). This 67 times productivity increase shows a successful

scale-up. The outcome of these experiments is noteworthy, as a

linear scale-up was achieved. The reaction ran smoothly,

implying that no unforeseen eﬀect occurred at any stage. As a

result, the use of such equipment is likely to be applicable to

related reactions, on other substrates. The ability to work

under these pressurized conditions increases ozone solubility

and has a positive result on the process productivity.

The ozone dosing line gas was switched on to let oxygen go

through the system. Both pump inlets were switched to reagent

and quenching solutions. The BPR was slowly set at the

desired pressure. After stabilization of the process (ﬂow rate),

The continuous ﬂow equipment used in these experiments is

inherently safer (e. g. due to its small volume and heat

management). Numerous detectors and automatic shutdown

procedures were intended to further mitigate process risks.

This in turn makes the ability to work with larger scale

equipment more likely to be successful.

These experiments reproducibly showed that varying the

conditions was successful and that a high percentage of ozone

in oxygen (10% wt) can be reached (Table 5). As the ozone

dosing line was built following a systematic analysis of the

NMR analysis was run and the “reference” sample (T ) was

taken for GCMS analysis.

The ozone gas generation was started. Peroxide tests were

carried out on a very regular basis (see Supporting Information

for more details). After stabilization at the appropriate ozone

concentration and ﬂow rate, NMR analysis was monitored to

check the reaction status. Reaction GCMS Samples were

594

Org. Process Res. Dev. 2021, 25, 1589−1597

Organic Process Research & Development

Article

collected (see Supporting Information for sample handling and

spectra).

Administration; IDLH, immediately dangerous to life or

health; PPE, personal protective equipment

When the trial was complete, the ozone generation was

switched oﬀ. The gas ﬂow was switched to nitrogen. The

reagent pump was switched back to the solvent. The back

pressure generator was set back at atmospheric pressure. The

system was let running for 15 min. Upon checking the absence

of peroxides in the collection tank, the quench pump ﬂow was

swapped to the rinsing solvent. The outlet diluting nitrogen

line was switched oﬀ. The dosing lines (ozone, reagent and

quench) were then switched oﬀ. Chillers and inline NMR were

switched oﬀ.

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ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

017, 73, 4233−4258.

■

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AUTHOR INFORMATION

Corresponding Author

Philippe M. C. Roth − Corning Reactor Technologies, Corning

■

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Authors

Margaux Vaz − Ecole Nationale Supérieure de Chimie de

ParisUniversité PSL, 75005 Paris, France; Present

Address: Ecole Nationale Superieure de Chimie de

ParisUniversite

PSL, 11 Rue Pierre et Marie Curie,

5005 Paris, France

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Daniel Courboin − Corning Reactor Technologies, Corning

SAS, 77215 Avon Cedex, France

Marc Winter − Corning Reactor Technologies, Corning SAS,

Complete contact information is available at:

7215 Avon Cedex, France

(

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Author Contributions

All authors equally participated in the experiments. M.V. and

D.C. designed the ozone dosing line. The manuscript was

written by P.R., M.V., and D.C.. All authors have given

approval to the ﬁnal version of the manuscript.

(

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Notes

The authors declare no competing ﬁnancial interest.

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NOTE ADDED AFTER ASAP PUBLICATION

■

This paper was published on the Web on July 2, 2021.

Numerous additional changes were made in the text as well as

the title. The corrected version was reposted on July 7, 2021.

597