1 3
Topics in Current Chemistry (2019) 377:2
(DMSO) and hypervalent iodine compounds, but are no less green. As social con‑
cern regarding the environmental impact of chemical processes gains more interest,
there is an increasing demand to design more sustainable chemical methodologies.
Anastas introduced the 12 principles of green chemistry, outlining the steps neces‑
sary for more sustainable synthesis practices [3]. Over the last 10–15 years, ground‑
breaking progress has been made in the development of highly selective aerobic oxi‑
dation reactions [4]. The replacement of toxic and corrosive stoichiometric oxidants
with processes that use O 2 combined with catalytic methodologies will ensure atom
efficient and selective synthetic oxidation approaches that are sustainable into the
future [5].
Oxidation chemistry utilizing pure O 2 or air as the oxidant source is already used
extensively within the bulk and commodity chemical manufacturing sector [6]. For
example, 6 basic chemicals are produced using pure O 2 and 12 chemicals using air
at > 2 Mt/a scale. In the bulk and commodity chemicals sector, the use of air and O 2
as the oxidant source is driven by the requirement to keep costs as low as possible.
However, O 2 is underutilized as an oxidant within the fine and pharmaceutical chem‑
ical industry. The bulk chemicals sector deals with low value, high volume products
and the corresponding production plants are generally designed and engineered as
dedicated continuous processes, whereas fine chemicals and the pharmaceutical sec‑
tor have historically favored the use of multipurpose batch reactors for the manufac‑
ture of high value, low volume products [7]. There are unique process challenges
associated with handling gas–liquid transformations within multipurpose batch reac‑
tors. Efficient mixing between the liquid phase and gas phase is difficult to achieve;
therefore, reactions are often mass transfer limited, which leads to problems when
scaling up from laboratory to manufacturing scale. The solubility of O 2 in water and
organic solvents is poor, thus the reactor needs to be pressurized to maximize the
amount of gas in solution to reduce mass transfer effects. Typical commercial scale
batch reactors can operate between 2 and 6 bar; therefore, higher pressures require
more specialized and expensive equipment. In addition, aerobic oxidation reactions
are typically highly exothermic, meaning the heat generated needs to be efficiently
removed. These challenges, and the fact that the reaction utilizes potentially flamma‑
ble O 2 under certain conditions, unfortunately increase the perceived scale‑up risk,
which has rendered the use of O 2 virtually unacceptable for pharmaceutical and fine
chemical synthesis.
The challenges associated with handling O 2 are better addressed by using contin‑
uous processing than multipurpose batch reactors [7, 8]. There is a current paradigm
shift in the pharmaceutical industry from traditional batch manufacturing to con‑
tinuous processing for the preparation of active pharmaceutical ingredients (APIs)
[9–12]. This paradigm shift is reflected by a new focus in the pharmaceutical indus‑
try on process intensification, sustainability, product quality, safety, energy usage
and cost [13]. The United States Food and Drug Administration (FDA) is taking
proactive steps to facilitate the implementation of continuous manufacturing within
the pharmaceutical industry as an attempt to improve product quality and reduce
the environmental impact of pharmaceutical manufacture [14]. The University of
Wisconsin‑Madison Oxidation Consortium (MadOx) involving Eli Lilly and Co.,
Merck and Pfizer was established in 2012 as a precompetitive collaboration aimed
69
Reprinted from the journal
Topics in Current Chemistry (2019) 377:2
(DMSO) and hypervalent iodine compounds, but are no less green. As social con‑
cern regarding the environmental impact of chemical processes gains more interest,
there is an increasing demand to design more sustainable chemical methodologies.
Anastas introduced the 12 principles of green chemistry, outlining the steps neces‑
sary for more sustainable synthesis practices [3]. Over the last 10–15 years, ground‑
breaking progress has been made in the development of highly selective aerobic oxi‑
dation reactions [4]. The replacement of toxic and corrosive stoichiometric oxidants
with processes that use O 2 combined with catalytic methodologies will ensure atom
efficient and selective synthetic oxidation approaches that are sustainable into the
future [5].
Oxidation chemistry utilizing pure O 2 or air as the oxidant source is already used
extensively within the bulk and commodity chemical manufacturing sector [6]. For
example, 6 basic chemicals are produced using pure O 2 and 12 chemicals using air
at > 2 Mt/a scale. In the bulk and commodity chemicals sector, the use of air and O 2
as the oxidant source is driven by the requirement to keep costs as low as possible.
However, O 2 is underutilized as an oxidant within the fine and pharmaceutical chem‑
ical industry. The bulk chemicals sector deals with low value, high volume products
and the corresponding production plants are generally designed and engineered as
dedicated continuous processes, whereas fine chemicals and the pharmaceutical sec‑
tor have historically favored the use of multipurpose batch reactors for the manufac‑
ture of high value, low volume products [7]. There are unique process challenges
associated with handling gas–liquid transformations within multipurpose batch reac‑
tors. Efficient mixing between the liquid phase and gas phase is difficult to achieve;
therefore, reactions are often mass transfer limited, which leads to problems when
scaling up from laboratory to manufacturing scale. The solubility of O 2 in water and
organic solvents is poor, thus the reactor needs to be pressurized to maximize the
amount of gas in solution to reduce mass transfer effects. Typical commercial scale
batch reactors can operate between 2 and 6 bar; therefore, higher pressures require
more specialized and expensive equipment. In addition, aerobic oxidation reactions
are typically highly exothermic, meaning the heat generated needs to be efficiently
removed. These challenges, and the fact that the reaction utilizes potentially flamma‑
ble O 2 under certain conditions, unfortunately increase the perceived scale‑up risk,
which has rendered the use of O 2 virtually unacceptable for pharmaceutical and fine
chemical synthesis.
The challenges associated with handling O 2 are better addressed by using contin‑
uous processing than multipurpose batch reactors [7, 8]. There is a current paradigm
shift in the pharmaceutical industry from traditional batch manufacturing to con‑
tinuous processing for the preparation of active pharmaceutical ingredients (APIs)
[9–12]. This paradigm shift is reflected by a new focus in the pharmaceutical indus‑
try on process intensification, sustainability, product quality, safety, energy usage
and cost [13]. The United States Food and Drug Administration (FDA) is taking
proactive steps to facilitate the implementation of continuous manufacturing within
the pharmaceutical industry as an attempt to improve product quality and reduce
the environmental impact of pharmaceutical manufacture [14]. The University of
Wisconsin‑Madison Oxidation Consortium (MadOx) involving Eli Lilly and Co.,
Merck and Pfizer was established in 2012 as a precompetitive collaboration aimed
69
Reprinted from the journal