Topics in Current Chemistry (2019) 377:2
1 3
at solving the challenges associated with aerobic oxidations in pharmaceutical man‑
ufacturing [15]. In particular, the consortium focused on the development of safe
and scalable continuous flow technologies for aerobic oxidation reactions. Recent
reviews have provided overviews of the significant progress made in the last decade
towards the utilization of O 2 within continuous flow environments [16–18].
A significant obstacle to the uptake of aerobic oxidation reactions is that under‑
graduate organic chemistry textbooks still teach classical oxidation methods, which
use toxic inorganic oxidants in stoichiometric quantities rather than more recently
developed greener aerobic oxidation strategies. Therefore, organic chemists lack the
necessary knowledge to implement these new greener methods. There are hurdles to
the implementation of large‑scale aerobic oxidations owing to the lack of experience
and equipment within pharmaceutical manufacturing. In this article, we highlight
selected synthetic examples of liquid phase aerobic oxidation reactions under con‑
tinuous flow conditions. The first section deals with the process aspects associated
with utilizing aerobic oxidation reactions, and also gives an overview of a typical
continuous flow setup for performing aerobic oxidations. Subsequently, homogene‑
ous catalysis and heterogeneous catalysis examples are discussed. The utilization of
photochemistry for the in situ formation of singlet oxygen (
1
O 2 ) from ground state
triplet oxygen (
3
O 2 ) is treated only briefly, owing to the large number of examples
published. The use of supercritical fluids and liquid carbon dioxide (CO 2 ) as green
solvents for aerobic oxidations is examined. Membrane technologies, new reactor
developments and scale‑up strategies are discussed. The advantages and challenges
associated with the utilization of continuous processing for liquid phase aerobic oxi‑
dations are highlighted throughout.
2 Process Aspects
2.1 Mass and Heat Transfer
The solubility of O 2 in organic solvents and water is generally very poor; therefore,
the reaction rate for liquid phase aerobic oxidations in many cases is determined by
mass transfer from the gas phase to the liquid phase [19]. The solubility of O 2 in the
liquid phase obeys Henry’s law whereby the amount of dissolved gas is proportional
to its partial pressure in the gas phase [20]. Continuous flow reactors have advan‑
tages over standard glassware and sealed batch autoclaves in terms of mass transfer,
even at a laboratory scale [21]. Within a batch processing environment, much of the
gas is in the headspace, thus the reactor needs to be pressurized to maximize the
amount of gas in solution. The rate of mass transfer from the gas phase to the liquid
phase is also dependent on the interfacial contact area between the gas and liquid
phases. The gas–liquid interfacial area to volume ratio decreases considerably with
increasing batch reactor size [22] (see Fig. 1). Consequently, the results achieved
within a small scale batch reactor are often irreproducible even within a laboratory
batch reactor of slightly different dimensions. The highly exothermic nature of many
aerobic oxidations also creates the need for efficient heat removal of the heat gener‑
ated in the reaction to avoid thermal runaways. The reduction in reactor surface area
70
Reprinted from the journal
1 3
at solving the challenges associated with aerobic oxidations in pharmaceutical man‑
ufacturing [15]. In particular, the consortium focused on the development of safe
and scalable continuous flow technologies for aerobic oxidation reactions. Recent
reviews have provided overviews of the significant progress made in the last decade
towards the utilization of O 2 within continuous flow environments [16–18].
A significant obstacle to the uptake of aerobic oxidation reactions is that under‑
graduate organic chemistry textbooks still teach classical oxidation methods, which
use toxic inorganic oxidants in stoichiometric quantities rather than more recently
developed greener aerobic oxidation strategies. Therefore, organic chemists lack the
necessary knowledge to implement these new greener methods. There are hurdles to
the implementation of large‑scale aerobic oxidations owing to the lack of experience
and equipment within pharmaceutical manufacturing. In this article, we highlight
selected synthetic examples of liquid phase aerobic oxidation reactions under con‑
tinuous flow conditions. The first section deals with the process aspects associated
with utilizing aerobic oxidation reactions, and also gives an overview of a typical
continuous flow setup for performing aerobic oxidations. Subsequently, homogene‑
ous catalysis and heterogeneous catalysis examples are discussed. The utilization of
photochemistry for the in situ formation of singlet oxygen (
1
O 2 ) from ground state
triplet oxygen (
3
O 2 ) is treated only briefly, owing to the large number of examples
published. The use of supercritical fluids and liquid carbon dioxide (CO 2 ) as green
solvents for aerobic oxidations is examined. Membrane technologies, new reactor
developments and scale‑up strategies are discussed. The advantages and challenges
associated with the utilization of continuous processing for liquid phase aerobic oxi‑
dations are highlighted throughout.
2 Process Aspects
2.1 Mass and Heat Transfer
The solubility of O 2 in organic solvents and water is generally very poor; therefore,
the reaction rate for liquid phase aerobic oxidations in many cases is determined by
mass transfer from the gas phase to the liquid phase [19]. The solubility of O 2 in the
liquid phase obeys Henry’s law whereby the amount of dissolved gas is proportional
to its partial pressure in the gas phase [20]. Continuous flow reactors have advan‑
tages over standard glassware and sealed batch autoclaves in terms of mass transfer,
even at a laboratory scale [21]. Within a batch processing environment, much of the
gas is in the headspace, thus the reactor needs to be pressurized to maximize the
amount of gas in solution. The rate of mass transfer from the gas phase to the liquid
phase is also dependent on the interfacial contact area between the gas and liquid
phases. The gas–liquid interfacial area to volume ratio decreases considerably with
increasing batch reactor size [22] (see Fig. 1). Consequently, the results achieved
within a small scale batch reactor are often irreproducible even within a laboratory
batch reactor of slightly different dimensions. The highly exothermic nature of many
aerobic oxidations also creates the need for efficient heat removal of the heat gener‑
ated in the reaction to avoid thermal runaways. The reduction in reactor surface area
70
Reprinted from the journal