LLNL-JRNL-830607

Recent advances in the

chemistry of hydrometallurgical
methods

G. Deblonde, A. Chagnes, G. Cote

January 7, 2022

Separation & Purification Reviews

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Recent advances in the chemistry of hydrometallurgical
methods
Gauthier J.-P. Deblonde1*, Alexandre Chagnes2, Gérard Cote3
1 Glenn T. Seaborg Institute, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory,
Livermore, California 94550, United States
2 CNRS, GeoRessources, Université de Lorraine, 54000 Nancy, France

3 PSL Research University, Chimie ParisTech – CNRS, Institut de Recherche de Chimie Paris, 11 rue Pierre et

Marie Curie, 75005 Paris, France

*E-mail: [email protected]

Abstract
Producing pure substances has been the obsession of scientists for centuries and has defined

chemistry as we know it. Nowadays, most of our economy still relies on the chemists’ ability to

extract and purify elements from raw or recycled materials, which, in most cases, is done partly or

entirely via hydrometallurgical methods. Here, the authors present the critical aspects of this

relatively overlooked, yet critical, chemistry discipline. This review article highlights the

importance of hydrometallurgical processes for strategic industrial sectors, put in perspective

traditional separation methods with emerging ones (new metal-binding chelators, ionic liquids,

deep eutectic solvents, microfluidic devices, biomaterials, etc.), critically reviews progress made

on separation methods over the past two decades, and highlights the challenges lying ahead for the

hydrometallurgists in academia and the industry.

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Introduction.
Science progress and the evolution of consumer habits have led us to a point where our economy,

means of communications, transport infrastructures, energy production and storage, defense

apparatus, and health care system depend heavily on advanced technologies which necessitate very

elaborated supply chains. And, while the retail value of a final product or its benefits to society

often come from the last few steps of the supply chain (manufacturing, marketing, branding,

distribution, etc.), most items in our daily life stem from a common first step: extracting and

purifying specific elements from raw sources or materials to recycle. For most metals, the first

product that can be commercialized and enters the supply chain is a mineral concentrate or purified

salt that is produced via hydrometallurgy (Figure 1). This often-overlooked chemistry discipline

consists of starting from a feedstock (typically a mineral ore or spent materials that has been pre-

concentrated by physical means like grinding, sieving, froth flotation, magnetic and eddy current

separations, etc.) and extracting its valuable elements by dissolution in an aqueous media followed

by multiple steps of selective solvent extraction, liquid-solid extraction, precipitation,

crystallization, or a combination of these techniques. Hydrometallurgical methods leverage

fundamental chemistry principles to achieve efficient separation such as differences in speciation,

binding affinity, hydrodynamic size, solubility, aqueous/organic partition, redox properties, etc.

Hydrometallurgy has been defined by opposition to pyrometallurgy, i.e., the historical route where

raw materials are refined at high temperatures and without solvent. Hydrometallurgical processes

present several advantages over pyrometallurgical ones: low energy consumption, low

temperature, scalability, modularity, operations in continuous settings, and high and tunable purity

for the final product(s). Hence, nowadays most elements are refined entirely or partially via

hydrometallurgy methods (Figure 1). This review article underlines the importance of

hydrometallurgical processes for strategic industrial sectors and research areas, contrast traditional

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separation methods with emerging ones (new metal-binding chelators, ionic liquids, deep eutectic

solvents, microfluidic devices, biomaterials, etc.), critically reviews progress made on separation

methods and processes over the past two decades, and highlights the challenges lying ahead for

the hydrometallurgists in academia and the industry.

Figure 1. A) Periodic table of the elements with emphasis on economically important elements that are
entirely or partially produced via hydrometallurgical methods (solvent extraction, selective precipitation,
ion-exchange, electrowinning, electrolytic refining, etc.). This list is not meant to be exhaustive. Stable
elements produced via hydrometallurgy and that have significant economic importance are highlighted in
green. Hydrometallurgicaly-produced radioactive elements with significant economic and/or strategic
importance are highlighted in both green and yellow. Radioactive elements used for research with minor
economic importance are highlighted in yellow. For clarity, medical radioisotopes that also have stable
isotopes (ex: 89Zr, 177Lu, 90Y) are represented in green, even if the production of most radioisotopes involves
hydrometallurgy methods; B) Cumulative number of publications listed in Web of Science for select topics
related to hydrometallurgy (Source: Web of Science. Number of hits given for the expression listed on the
graph, in the category “Topic”. Search updated on: April 5th, 2022).

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Strategic sectors relying on hydrometallurgical methods.
Critical materials production and purification.
One of the most apparent changes that the hydrometallurgy field experienced within the past few

decades is that it has been projected on the world’s stage due to the rare earth elements (REEs)

and associated geopolitical tensions between China (the current world’s top producer) and

countries that do not have a significant REE production and purification capacity. REEs

(scandium, yttrium and the lanthanide elements) are so chemically similar that their separation at

industrial scale can only be performed via hydrometallurgy, i.e. usually a multi-stage solvent

extraction process[1]. Given that REEs are used in numerous key applications (catalysts, hard

drives, magnets, screen displays, electric engines, wind turbines, polishing, optics, etc.),

hydrometallurgical methods capable of separating them from one another have become highly

strategic, with both scientific and political implications. The REEs are part of a larger group of

“critical materials” identified by western countries (mainly the United States and European Union)

because of their economy strongly relies on the importation of these materials, hence creating a

critical and fragile link in strategic supply chains (automobile, energy, defense sectors, etc.).

Starting in 2011, the EU published its first list composed of 20 raw materials and has continued to

update this list since then. In 2020, the EU published its 4th “critical raw materials” list, which has

grown to 30 types of materials, including 16 that are mainly produced via hydrometallurgy:

antimony, bismuth, cobalt, gallium, germanium, hafnium, heavy REEs, indium, light REEs,

lithium, niobium, platinum group metals, scandium, tantalum, titanium, and tungsten. Figure 2

gives an overview of the EU critical material list, in a 2D version of the typical critical material

assessment framework (which initially had a 3rd dimension for “environmental implications” [2, 3]).

This kind of diagram is often cited to demonstrate the economic importance of REEs in western

countries and the fragility of the REE supply chain. However, this representation also illustrates

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that the REEs topic is only a fraction of a bigger issue as, for instance, ~10 other elements have

higher economic importance than the REEs and are also subject to supply tensions in the EU.

Figure 2. Raw materials considered as critical by the European Union, as of 2020. This plot was published
by the European Commission in its detailed report entitled “Study on the EU's list of critical raw materials
(2020)”[4].

Similar to the European Union, the United States strongly relies on importations for strategic

elements that make them “critical” (Figure 3). In 2018, the US Department of interior released a

list of 35 mineral commodities that it considers critical to the economy and national security of the

US[5–7]. The list includes the following: aluminum, antimony, arsenic, barite, beryllium, bismuth,

cesium, chromium, cobalt, fluorspar, gallium, germanium, graphite, hafnium, helium, indium,

lithium, magnesium, niobium, the platinum group metals, potash, the REEs (including scandium),

rhenium, rubidium, strontium, tantalum, tellurium, tin, tungsten, uranium, vanadium, and

zirconium. In late 2021, the USGS also published[8] a proposed updated list of minerals to be

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considered as critical in the US (Figure 3), and this draft list is largely consistent with the 2018

list with the addition of nickel and zinc to the list. The top five elements in terms of supply risk in

the US are: gallium > niobium > cobalt > neodymium > ruthenium. One can note that most of the

elements included in the US critical mineral list are produced via hydrometallurgy. Interestingly,

Canada, which has an extensive mining industry, also has a list of minerals that are considered

critical to the sustainable economic development of Canada and its allies. The most recent

Canadian list of critical materials, released in early 2021[9], is composed of 31 elements and is

relatively similar to that of the 2018 US list, except for the inclusion of copper, molybdenum,

nickel, and zinc, and the absence of arsenic, barite, beryllium, hafnium, rhenium, rubidium,

strontium, and zirconium, relative to the 2018 US list of critical mineral commodities. This binary

example highlights that material criticality is a truly relative term that mainly stems from the

inequal distribution of natural resources around the globe, but that it can also be alleviated via

international cooperation.

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Figure 3. Evaluation of the supply risk for 54 mineral commodities in US. The economic vulnerability is
plotted against the disruption potential. The point size corresponds to the trade exposure. The color of each
point indicates the overall supply risk. This plot was published by U.S. Geological Survey in its 2021 report
entitled “Methodology and Technical Input for the 2021 Review and Revision of the U.S. Critical Minerals
List” [8]. The readers are also invited to read the prior report from the U.S. Geological Survey entitled
“Mineral commodity summaries 2020”[10].

While China is often put under the spotlight for its monopolistic position on the REE production,

it is often forgotten that China also relies on importations for other elements. Figure 4 depicts the

list of elements considered as critical for the Chinese economy. Unsurprisingly, the REEs are not

considered as particularly critical in China (its supply risk being minimal since China is currently

the world’s top producer) and the list is significantly different from those of the western countries.

The Chinese economy particularly relies on importation for the platinum group metals (PGMs),

niobium, and cobalt, and, to a lesser extent, for germanium, zirconium, selenium, and chromium.

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Figure 4. A) 3D criticality framework for raw materials in China. B) 2D version of the criticality matrix
for raw materials in China. Graphs published by Yan et al. [11]. Copyright 2021 Cell Press.

The tensions related to critical materials has led to strong initiatives with the implementation of

academic collaborations, industry-academia partnerships, and industrial hydrometallurgy

networks that aim at creating domestic supply chains of critical materials. In the US, the

Department of Energy’s Critical Materials Institute focuses on "critical" rare earths and "near-

critical" materials (REEs, indium, gallium), as well as metals and graphite used in battery materials

(lithium, cobalt, manganese) by “diversifying supply, developing substitutes, driving reuse and

recycling and crosscutting research”. The European Commission launched in 2014 the “Horizon

2020” program dedicated to fund interdisciplinary research and innovation programs in order to

address economic and societal challenges, including the sustainable supply of raw materials. The

new research and innovation program “Europe 2030” has started in 2021 with the creation of the

European Raw Material Alliance (ERMA), to make the “EU more economically resilient by

diversifying its supply chains, creating jobs, attracting investments to the raw materials value

chain, fostering innovation, training young talents and contributing to the best enabling

framework for raw materials and the circular economy worldwide with a special focus on the

supply of raw materials for energy transition”. These initiatives aim at securing a supply of critical

elements for the energy transition and national security reasons but came with the immense

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scientific challenge to rapidly develop separation processes that are tailored to domestic

feedstocks, and it has greatly stimulated the research field over the past decade (vide infra).

While REEs routinely catch the media attention, other elements produced by hydrometallurgy are

almost unknown to the general public but are nonetheless highly strategic and have nearly

monopolistic supply chains. Notably, niobium and tantalum – two metals used in electronic

components, optical lenses, supra-conducting magnets, magnets used for medical imaging devices,

high-strength low-alloy steels for cars, airplanes and missiles – are produced by a very small

number of countries: 88% Brazil, 10% Canada for niobium; 40% Congo, 20% Rwanda, 14%
[10]
Brazil, 12% Nigeria for tantalum in 2019 . Figure 5 highlights the strategic importance of

niobium and tantalum as both the United States and China rely entirely on importations for these

two elements. The European Union also imports >99% of its niobium and tantalum[4]. Likewise,

hafnium is a highly strategic element as it is used in nuclear reactor control rods, cutting tools, and

high-temperature alloys, but it is mostly produced in the USA and France. Hafnium is mainly

recovered as a by-product of the production of high-purity zirconium, which is required for nuclear

fuel claddings. The criticality of hafnium is therefore even higher than that of zirconium. The

separation of these two elements is also not trivial, reminiscent of the separation of two adjacent

REEs, since Hf and Zr are two elements of the same column and have nearly identical chemical

properties (same +IV oxidation state, similar ionic radius, etc.). For these strategic but rather

discreet metals, new hydrometallurgical processes for extraction from secondary sources or

recycling from end-of-life products could become highly disruptive.

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Figure 5. Comparison of the importation of 42 mineral commodities by the United States and by China.
The data correspond to importations for the year 2014. Some of these materials are now considered as
critical by the United States and/or China. This plot was originally published by Gulley et al. [12]. Copyright
2018, PNAS.

Materials for energy storage.

The storage of energy, especially in the form of electricity, is largely seen as an essential

component of the energy transition. In particular, two emerging sectors will be particularly reliant

on energy storage (i.e., electric batteries): electric vehicles and storage of electricity from

intermittent energy production (e.g., solar panels and wind turbines). In this context, lithium-ion

batteries are of paramount importance. This technology is now mature although there are still many

challenges to increase their energy density while ensuring the highest safety standards. As such, it

is necessary to develop new electrode materials that can be cycled at higher voltages and

electrolytes compatible with these materials. It also appears crucial to develop sustainable, cost-

effective, and efficient Li extraction and purification processes to be able to meet the current

lithium demand, respond to the growing market expansion, and establish reliable lithium supply

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chains. Hydrometallurgical processes for Li production will be key to avoid a situation similar to

that of the REEs. Moreover, these challenges are not limited to lithium since the production of Li-

ion batteries also relies on other critical resources like nickel, manganese, and cobalt.

With regard to primary extraction, lithium is commercially produced from two main sources: (i)

solid mineral ores containing spodumene (LiAlSi2O6) or petalite (LiAlSi4O10), and more recently

Jadarite (LaNaSiB3O7(OH))[13, 14]; (ii) subsurface brines which have become the dominant raw

material for lithium carbonate production worldwide because of lower production costs compared

to the mining and processing costs associated with hard-rock ores. The ores are processed by

combining a thermal treatment and a hydrometallurgical process whereas the brine treatment

involves solar evaporation for as long as 12-18 months to produce lithium chloride, followed by

lithium chloride refining, and conversion stages to produce high-grade lithium salt via

hydrometallurgical processing.

Among the different lithium ores, the mineral spodumene is one of the most potent and is relatively

abundant, particularly in Australia. The main process used for lithium recovery from spodumene

has been described in detail by Chagnes[15] and Fosu et al. [16]

. Briefly, it is based on a series of

operations including beneficiation, roasting at 1070-1090 °C to convert spodumene to its beta form

(this operation is accompanied by severe decrepitation, which leaves spodumene very finely

pulverized), acid leaching with H2SO4 under at about 250°C under pressure, dilution with water,

elimination of metallic impurities (Fe, Al, Mg, Ca…) by hydroxide precipitation at pH 12 by

adding NaOH or by co-precipitation using limestone and, finally, recovery of lithium with ion

exchange resins.

Production of battery-grade lithium salts from brines relies on natural evaporation followed by

solvent and/or resin extraction steps. Solar evaporation is very inexpensive, but it requires >12

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months from the start of the operation to the production of the lithium salt. Moreover, conventional

lithium extraction processes which rely only on solar evaporation are only applicable to specific

geographical areas (e.g., high altitude and dry weather). In order to circumvent the evaporation

step and shorten the production time, two innovative industrial processes have been recently

developed, as detailed below.

The ERAMET Process [18]: This mining and metal refining company started developing a lithium

production project in order to extract lithium from brines located in the Andean cordillera area

(Salta, north-western Argentina). The resources of the Centenario-Ratones deposit are significant

and could yield 20,000 tonnes of lithium carbonate per year for several decades. The core

innovation of this process is a sorption material selective towards lithium (general formula

LiCl.2Al(OH)3,nH2O) implemented in a solid-liquid extraction, and membrane stages. The brine

is pumped from a depth of 200 m and is fed into the lithium extraction unit consisting of a

solid/liquid extraction step using the Li+-selective sorbent[18]. During this step, lithium is

selectively extracted relative to calcium, magnesium, boron, and sulphates. The Li-depleted brine

is then reinjected in the original field aquifer via infiltration so that the water balance of the brine

field is not affected (unlike conventional solar evaporation processes which deplete the aquifers).

After elution of the lithium-loaded sorbent, the solution is concentrated via reverse osmosis and

the resulting concentrated solution is subsequently purified via solvent extraction (to remove boron

traces) and ion exchange extraction (to remove traces of calcium and magnesium). A final addition

of sodium carbonate produces high-purity lithium carbonate salts for use in glass, ceramic, and

greases applications as well as lithium-ion batteries.

The Solvay-Tenova Process [19, 20]: This new technology for lithium recovery from brine is based

on Cyanex® 936— a phosphorus-based extractant specifically formulated for lithium, which

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exhibits a good extraction efficiency for lithium (80% at pH 9) and high selectivity against

potassium, sodium, and boron ions. This solvent extraction process is combined with membrane

technologies and electrolysis. Calcium and magnesium are first removed from the brine by a

membrane filtration. The brine without magnesium and calcium is then sent into an electrolysis

cell to generate chlorine and then hydrochloric acid by-products (which is recycled as stripping

reagent in the downstream solvent extraction step). The purified pregnant leaching solution

containing lithium is sent to a solvent extraction stage that relies on the extractant Cyanex® 936.

After scrubbing and stripping with hydrochloric acid, lithium chloride is directly produced, or the

stream can be sent to a precipitation stage to produce lithium carbonate or to an electrolysis stage

to produce hydrochloric acid and lithium hydroxide. This process is also advantageous as it allows

for the extraction of lithium without affecting the water balance of the brine field, similar to the

ERAMET process. Both processes avoid slow production kinetics inherent to solar evaporation.

They are also more versatile than conventional evaporation-based processes since they can

produce multiple products, at various grades, without significantly changing the process scheme.

Processes circumventing the evaporation step may supplant traditional lithium extraction

processes in the future as the growing lithium demand will inherently require mining companies

to diversify their primary sources, outside conventional brines, such as geothermal brines or even

second-hand materials to recycle.

Radiochemistry applications
The use of hydrometallurgy goes well beyond the bulk production of metal commodities, and it is

also a convenient technique to refine materials for high-value elements. As such, the nuclear

energy sector also depends heavily on hydrometallurgical methods throughout the nuclear fuel

cycle, beginning with the mining and purification of natural uranium from mineral deposits, and

ending with the reprocessing of spent nuclear fuel rods to recover their valuable components (U

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and Pu isotopes) and isolate the most dangerous ones (fission products, activation products, heavy

actinides). As such, one of the most iconic hydrometallurgical processes is the PUREX process

(Plutonium Uranium Reduction and EXtraction process - also known as Plutonium

and Uranium Recovery by EXtraction) which has been used in multiple countries since the 1950’s

and is still the harbinger of large-scale nuclear reprocessing plants at La Hague (France) and

Ozersk (Mayak, Russia) which can treat a combined 2100 tones (expressed in tHM)[21] of spent

light-water reactor nuclear fuel per year, with an additional capacity of 800 tHM/year expected

with the start of Rokkasho (Japan) in 2022. Detailed information about the hydrometallurgical

processes in nuclear fuel processing, can be found in the three recent reviews from Taylor et al.[22]

, Geist et al.[23], and Baron et al.[24].

On the fundamental research front, an international race to create new elements has been launched

since the era of the Manhattan Project. Since then, the expansion of the periodic table as we know

it has been driven by our ability to produce heavy actinide targets of high purity (e.g. 244Pu, 243Am,
248
Cm, 249Bk, 249Cf, etc.) that are then bombarded with lighter elements (e.g. 22Ne, 26Mg, 48Ca) to

create synthetic “super-heavy elements” (Z > 103)[25]. Milligram quantities of the heavy isotopes

used in targets are extracted and purified from irradiated research nuclear fuels via

hydrometallurgy and notably solvent extraction and ion-exchange[26]. Over the past few decades,

Oak Ridge National Laboratory (Tennessee, USA) has been at the forefront of these radio-

hydrometallurgical purification processes[27] and, interestingly, element 117 has been officially

named “tennessine” in 2016, not to give credit the place where it was first synthesized (Dubna,

Russia), but to acknowledge the place that produced and purified the target (made of 249Bk).

The hydrometallurgical production of very high-purity and high-value materials is also paramount

to modern medicine. Over the past two decades, the medical imaging and nuclear medicine sectors

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have experienced substantial growth[28, 29]. Imaging techniques, such as MRI and PET scans are

now considered routine and highly innovative cancer treatments like beta or targeted alpha

therapies have emerged in the past two decades. This has led to the development of an entirely

new hydrometallurgy sector that aims at producing and purifying minute quantities of very high-

purity (and high-value) short-lived isotopes (44/47Sc, 67/68Ga, 89Zr, 177Lu, 212Pb, 213Bi, 223Ra, 227Th,
225
Ac, etc.)[29–31] that are crucial to medicine. Actinium chemistry has recently caught the most

attention due the promising use of its short-lived isotope 225Ac (t1/2 = 10 days) in next-generation

cancer therapies. Notably, resounding results have been obtained by Kratochwil et al.[32] on the

treatment of metastatic prostate cancer, and a flurry of initiatives have been launched by several

countries to produce and hydrometallurgicaly purify actinium isotopes in order to fulfill future

hospital needs and also to help studying actinium chemistry[30, 33–44]. This growing field is at the

crossroad of radiochemistry, pharmaceutical production, separation sciences and is adapting

traditional hydrometallurgical methods to comply with the peculiarities and stringent

specifications of radiopharmaceuticals.

Emerging technologies for hydrometallurgical separations

Novel super-selective extractants.
Despite remaining in the shadow of other chemistry disciplines, hydrometallurgy is nonetheless a

very active field as it is continuously challenged by the evolving customer habits, sporadic

consumption spikes and shortages for certain tech-metals[45], geopolitical tensions, as well as

decreasing natural resources. This drives the research efforts on the development of more efficient,

selective, and cost-effective purification processes. At the heart of metal separation processes

involving liquid-liquid extraction or chromatography are the molecules participating in the transfer

of the metal ions between the two phases. A natural starting point for process optimization is

therefore the extractant(s) present in the organic phase. Industrial solvent extraction processes

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mostly rely on less than ten types of extractant molecules. Table 1 gives an overview of the

extractant molecules currently in use in the industry.

Table 1. List of the main extractants used in industrial hydrometallurgical processes. Additional
information given in ref. [46]. a: initially commercialized by the company “Cytec Industries Inc.”, recently
acquired by the “Solvay”.

Page 16 of 51
 Name of the extractant Composition Targeted metals and comments
(company)
Oximes
LIX63 Alkyl- -hydroxyoxime Ge, Cu, U-Mo separation from
H2SO4
LIX84-I Ketoxime-based reagent Cu from dilute H2SO4, nitrate,
without modifier ammonical leach solutions
Pd from acidic chloride solutions
LIX 84-INS Ketoxime-based reagent Ni from ammoniacal solutions
without modifier followed by acid stripping
LIX
LIX 84-IT Ketoxime based reagent+ester
(BASF)
modifier
LIX 860N-I; Aldoxime based reagents Cu extraction
LIX 860-I (based on 5-
nonylsalicylaldoxime for LIX
860-I and 5-
dodecylsalicylaldoxime for
LIX860N-I
Acorga M5640, Aldoxime+modifier Cu (mainly from Chile)
M5774, M5970
Acorga M5850, Aldoxime+modifier Cu
M5050
Acorga NR10, Aldoxime+modifier Cu (extraction solvent resistant
NR20 towards nitration)
Acorga
Acorga OR15, Aldoxime+modifier Cu (extraction solvent resistant
(Solvay)a
OR25 towards oxidation)
Acorga OPT Mixture of aldoxime and Cu (mainly from Africa)
ketoxime+modifier
Acorga Aldoxime+modifier Cu (where plants are located at
PT5050, high altitude where temperature
PT5050MD reaches 5 °C like in Chile)
Amines
Alamine 308 Tri(iso-octyl)amine Co-Ni separation from chloride
(branched alkyl chains) Zn recovery from spent
electrolyte solution
Alamine 336 Tri(n-octyl/n-decyl)amine Recovery of U, Mo from acidic
(linear alkyl chains) sulfate leach liquors
Recovery of V(V), W from
Alamine and
acidic leach liquors
Aliquat
Separation of Mo and Rh
(BASF)
Recovery of Au from acidic
thiocyanate leach liquor
Recovery of Ga from acidic
chloride solution
Alamine 304 Tri(n-dodecyl)amine Recovery of Mo from acidic
(linear alkyl chains) sulfate leach liquor

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 Aliquat 336 Tri(n-octyl/n-decyl) methyl Recovery of Mo, V(V), rare
ammonium choride earth from acidic sulfate leach
liquor
Removal of arsenic
LIX 7820 Mixture of a quaternary amine Au extraction from cyanide
LIX
and nonylphenol solution, thiosulfate solution and
(BASF)
cyanide recovery
Organophosphorus compounds
Cyanex 272 Bis(2,4,4-trimethylpentyl) Separation of cobalt and nickel
phosphinic acid from sulfate and chloride media
Cyanex 301 Bis(2,4,4- Extraction of heavy metals vs.
trimethylpentyl)dithiophosphi earth-alkali metals
nic acid Extraction of Zn at low pH
Cyanex Cyanex 921 Tri-n-octyl phosphine oxide U from wet phosphoric acid, Nb-
(Solvay)a Ta separation from HF/H2SO4
solution
Cyanex 923 Mixture of trialkylphosphine Extraction of Rh, As, Cs; Li, Cd
oxides (alkyl = normal, C6, and more than 30 other metals
C8) by playing on the redox and the
medium (chloride or sulfate).
PC-88A (2-Ethylhexyl)phosphonic acid Cobalt extraction from sulfate
mono-2-ethylhexyl ester acidic media
PC-88A Extraction and separation of rare
(Daihachi) earth
Extraction of In, Mo and other
metals
D2EHPA D2EHPA Bis(2-ethylhexyl)phosphoric Extraction of U, Zn, Fe, Ca, Be,
(Lanxess) acid Co, Mo
TBP Tri(n-butyl)phosphate Separation of U and Pu from
TBP
spent nuclear fuel
(Daihachi and
Separation of rare-earth
Lanxess)
Extraction of As, Cr, PGM
Dialkylsulfides
SFI SFI-6, SFI-6R Dihexylsulfide Separation of Pd from Pt
(Daihachi) Extraction of chloride complex
ions of Au, Ag, Cu, Hg and
others

However, discovering the optimal extractant for a specific metal of interest is an incredibly

challenging process, that usually goes from the selection of extracting functionalities and multiple

molecule backbones leading to numerous potential combinations, the design of synthetic

procedure for the new extractant (and oftentimes its precursors), performing the synthesis,

purifying the compound (if successful synthesis), and testing it for extraction of the metal(s) of

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interest and its potential impurities. Moreover, not all molecules are suitable for liquid-liquid

extraction as the cost and physical properties of the extractant itself also impose strict constraints

(e.g., solubility in the organic solvent versus aqueous phase, viscosity, solubility of its metal

complexes). Reminiscent of a drug development process, most of the potential extractants that are

considered in the beginning of the process do not meet the expected performance criteria.

Additionally, even for the molecules suitable for liquid-liquid extraction, predicting their

extraction efficiency and selectivity is nearly impossible as the phenomena involved are numerous,

complex, and often correlated to each other (e.g., aqueous complexation, mass transfer between

the two phases, metal coordination in the organic phase, co-extraction of water or salts, salting-out

effects, long-range organization of the extractant, formation of micelles). A recent study from

Stamberga et al.[47] showed that even for a well-known REE extractant, called “TODGA”

(trioctyldiglycolamide), subtle modifications of its alkyl sidechains, which at first sight do not take

part in the metal extraction mechanism, can drastically influence the REE extraction efficiency

and the selectivity of the extractant for the different REEs (Figure 6).

Page 19 of 51
Figure 6. Impact on the modification of the alkyl chains (considered as non-coordinated to the extracted
metal ions) of the diglycolamide extractant TODGA on the extraction coefficient and selectivity of the
lanthanide ions. D represents the distribution ratio, i.e., the ratio of the metal concentration in the organic
phase and concentration in the aqueous phase. Adapted with permission from ref. [47]. Copyright 2020
American Chemical Society.

Another example illustrating the dramatic influence of subtle modifications of side alkyl chains on

the extraction properties is given in Table 2, concerning the extraction of uranium(VI) and iron(III)

from 5 M phosphoric acid using bi-functional carbamoylalkylphosphonate extractants recently

reported by Turgis et al.[48]. Indeed, the modified extractant bearing a methyl group between the

carbamoyl and phosphonate functions exhibits a distribution ratio of uranium 10 times higher and

a U(VI)/Fe(III) selectivity 80 times higher than the similar extractant without the methyl group.

On the other hand, the replacement of the methyl group by a phenyl group decreases the

distribution ratio of uranium by a factor of ~2 but doubles the selectivity uranium/iron. In a similar

way, the mere branching of the C8 alkyl chains on the amide group leads to a U(VI)/Fe(III)

selectivity 7 time higher, while the distribution ratio is kept constant[48]. Such dramatic and non-

Page 20 of 51
linear effects cannot be anticipated prior to experimental testing. These unforeseen effects are not

only interesting from a fundamental point of view, but they also create intellectual property

conundrums as the generalization of the properties of one extractant to its structural derivatives (as

often claimed in patents) becomes questionable.

Table 2. Impact of the modification of the alkyl chains of the bis-functional liquid-liquid
carbamoylalkylphosphonate extractant on its performances for the extraction of uranium(VI). The uranium
distribution ratio (DU) and the separation factor between iron(III) and uranyl ions (SFU/Fe) are taken as the
main indicators for the extractant performance. Table adapted from the results published by Turgis et al.
[48]
. Conditions: [U] = 250 mg/L. [Fe(III)] = 2500 mg/L. Aqueous phase: 5 M H3PO4. Organic phase: 0.25
M extractant in dodecane. O/A = 1. For the sake of comparison DU = 3.8 and SFU/Fe = 200 for the mixture
of HDEHP/TOPO in kerosene under the same experimental conditions.

O O
R1 C P
N R4
OH
R2 R3 Extraction
Extractant : performance
R1 = R2 = R3 = R4 = DU SFU/Fe
EtHex EtHex H OH 2 1.5
EtHex EtHex CH3 OH 5.4 1
EtHex EtHex Ph OH 8 80
EtHex EtHex H OEt 12.2 10
EtHex EtHex CH3 OEt 120 800
EtHex EtHex Ph OEt 65 1800
EtHex EtHex Oct OEt 120 1900
EtHex EtHex H OBu 24 10
EtHex EtHex Oct OBu 117 2800
Oct Oct Oct OBu 116 400

These examples[47, 48], among others, illustrates the difficulty in developing solvent extraction

systems, and the emergence of new extractants in hydrometallurgy has been hindered, not only

because of the cost of associated with developing new molecules, but also because optimization

studies are still largely based on labor-intensive laboratory tests, educated guesses, and trials and

errors. In this regard, the hydrometallurgy field will likely benefit from future progress in

molecular modeling and the increase in computing capabilities.

Page 21 of 51
Novel super-selective aqueous chelators.
Another option for improving the selectivity of solvent extraction systems is to use a metal chelator

in the aqueous phase (also called “hold-back reagents” or “masking agents”). This configuration

is typically more expensive as it requires both a metal extractant and water-soluble metal chelator

and it is therefore reserved for the most arduous metal-metal separations and for high-value

elements. This configuration is also often used for chromatographic separations where the small

scale of the process and low metal concentration allow for the addition of an aqueous chelator in

the mobile phase without significantly increasing the overall cost of the separation. This approach

is particularly useful for the analysis of REEs where the separation of all the lanthanides can be

achieved by ion-exchange chromatography in the presence of simple carboxylic acids like oxalic,

α-butyric, tartaric, and/or nitrilotriacetic acids[49]. The use of hold-back reagent is also currently

the most performant option for the separation of americium and curium, in the context of high-

level nuclear waste recycling. The separation of these two actinides, which are adjacent in the

periodic table, is reputedly one of the most challenging of the periodic table (even more demanding

than separating two adjacent lanthanides) due to the radioactive nature of these elements and the

very small size difference between their ions. The ionic radius of the nine-coordinated Cm3+ is

1.147 Å, which is just 0.9% smaller than Am3+ (1.157Å)[50]. For comparison, the equivalent

lanthanide ions, Gd3+ and Eu3+, measure 1.101 Å and 1.116 Å, respectively, i.e., the size difference

is almost twice as big as that between Am3+ and Cm3+.

One of the handful Am/Cm separation processes that has been validated using genuine nuclear

spent fuel waste, is the so-called “ExAm” process (Extraction of Americium) developed by the

French Atomic energy Commission (CEA) since the late 2000’s[51–56]. While historical efforts on

hold-back reagents have been limited to carboxylate ligands, aqueous chelators with new metal-

binding functionalities have been investigated in recent years for the purpose of metal purification.

Page 22 of 51
For instance, in this process, the water-soluble chelator “TEDGA”, a diglycoamide derivative, is

used in combination with a mixture of two organic extractants (DMDOHEMA and HDEHP)

(Figure 7). The presence of TEDGA in the aqueous phase decreases the overall extraction of both

Cm3+ and Am3+ but the complexation of Cm3+ to TEDGA is stronger than that of Am3+, yielding

slightly higher extraction yields for Am3+ and separation of the two elements. The separation factor

Am/Cm after a single bath extraction is about 2.3, which is low but enough to separate the two

elements in a continuous flow setting. Despite its apparent complexity and low selectivity, this

process has been tested and validated in hot cells on genuine high-level radioactive waste solutions

(PUREX raffinate)[56–58], using a 32-stage extraction unit for the Am3+/Cm3+ separation. The Am

recovery was >99% and the overall decontamination factor Am/Cm was ~500.

Figure 7. Distribution ratio Am3+ and Cm3+ and associated separation factor (SFAm/Cm) obtained with the
extraction system DMDOHEMA/HDEHP/aqueous diglycoamide-based ligand. The formula and names of
the aqueous ligands are given at the bottom. Conditions: 0.6 M DMDOHEMA, 0.45 MHDEHP. Diluent =
hydrogenated tetrapropylene. Aqueous phase: 6 M HNO3. T = 25 °C. 30 mM diglycolamide, trace amounts
of 241Am and 244Cm. Adapted with permission from ref. [54]. Copyright 2016 Elsevier.

More recently, Jensen et al.[59] obtained, in batch extraction tests, a record separation factor for a

single extraction step of 4.1 between Am3+ and Cm3+ by using an aqueous chelator developed in-

house called “bp18c6” (N,N′-bis[(6-carboxy-2-pyridyl)methyl]-1,10-diaza-18-crown-6) (Figure

8). Unlike TEDGA and its derivatives, the aqueous chelator bp18c6 displays higher affinity for

Page 23 of 51
the larger cations (log β(AmL+) = 15.5 vs. log β(CmL+) = 14.9) [59] so that it yields better separation

if used in combination with common extractants like HDEHP which exhibits higher extraction

efficiency for the smaller cations. Contrary to the ExAm process, this approach allows for the

preferential extraction of Cm3+ in the organic phase while retaining the Am3+ complex(es) in the

aqueous phase. While very promising for the treatment of nuclear waste and removal of Am, the

ligand bp18c6 has only been tested at trace levels of Am and Cm isotopes and its performance

would need to be tested in a continuous flow process and at concentrations close to what is

expected in the treatment of nuclear waste.

Figure 8. A) Formula of the water-soluble ligand “bp18c6” developed by Jensen et al. [59] for the separation
americium/curium. This ligand was later renamed “macropa”. B) Distribution ratio of trivalent americium,
curium, and lanthanide ions using the H2bp18c6/HDEHP extraction system. Note that the higher extraction
yield as the metal ion gets smaller (from La3+ to Gd3+) is mainly due to the stronger complexation of
H2bp18c6 to the larger ions. Conditions: 0.05 M HDEHP in o-xylene/0.001 M H2bp18c6 in 1 M NaNO3,
0.05 M lactate at pH 3.0 and 23 °C. Squares: lanthanides measured by ICP-MS. Triangles: 152/154Eu
radiotracer. Circles: 241Am and 244Cm radiotracers. Adapted with permission from ref. [59]. Copyright 2016
American Chemical Society.

Page 24 of 51
In line with the work from Jensen et al., the chelator bp18c6 has been further studied in recent

years by Wilson and co-workers[60, 61] for the separation of REEs due its unusual preference for

the large cations over the small ones (i.e., preference for the light REEs over the heavy REEs, due

to the lanthanide contraction), which is the opposite of the trend observed for more classic metal

chelators like the polyaminocarboxylates[62, 63]. The name “bp18c6” was changed to “macropa” to

reflect the presence of a macrocycle and picolinate arms in the molecule (Figure 9). Additional

derivatives of macropa were synthesized (Figure 9A) and they also display unusual affinity trends

along the REE series owing to different binding modes of the REE3+ ions to the aza-crown-ether

macrocycles[60]. For examples, the ligands “macrodipa” and “macrotripa” exhibit a V-shape

selectivity along the lanthanide series with minimal affinity around Er3+ and Gd3+, respectively

(Figure 9B). This kind of ligands could be advantageous for next-generation REE or actinide

separation processes if used in combination with an organic extractant, similar to the ExAm

process. Another application taking advantage of the preference of the aza-crown-ether

macrocycle ligands for the large cations is the use of macropa for the binding of the medically

relevant actinium. The actinium ion, Ac3+, is the largest cation among the trivalent lanthanides and

actinides[39, 64]. Efficient chelators for Ac3+ are difficult to develop since classic ligands, like

carboxylates, have a strong preference for the small cations, leading to weak Ac3+ complexes[37,
41]
. This is particular issue for the chemical purification of actinium isotopes as well as the

production of 225Ac-radiolabeled drugs used in emerging cancer treatments[32, 65]. However, Wilson

et al. recently demonstrated[66] the suitability of the macropa ligand for Ac3+ chelation and

confirmed its in vivo stability, representing a significant step forward in this field of research. This

example perfectly illustrates the far-reaching ramifications that can have hydrometallurgical

studies, going from nuclear waste treatment[59] to medicine[66].

Page 25 of 51
Figure 9. Recently developed aqueous chelators with a reverse selectivity for the lanthanide ions (i.e.,
higher affinity for the small lanthanides compared to the larger ones). A) Structures of the recently
developed chelators macropa, macrodipa and macrotripa, and comparison with traditional carboxylic acid,
EDTA and OBETA. B) Logarithm of the formation constants of 1:1 complexes (KLnL) formed with the
aqueous chelators, plotted as a function of the ionic radii of the Ln3+ ions. Adapted with permission from
ref. [60]. Copyright 2020 American Chemical Society.

In another recent example of the use of aqueous chelator to improve selectivity of extraction

systems, it was demonstrated[67] that the octadentate ligand hydroxypyridinonate (HOPO) ligand

called “3,4,3-LI(1,2-HOPO)” (formula: C34H40N8O124-) yields ultra-selective separation systems

for high-value actinides, such as actinium, plutonium, and berkelium. In this case, this particular

molecule was selected for its strong preference toward the tetravalent ions over other cations

(divalent, trivalent, and actinyl ions). This ligand is particularly suitable for the rare isotopes of

berkelium as it is the only documented organic ligand that is capable of mediating the oxidation

of Bk3+ (the regular oxidation state of Bk) and stabilizing it as Bk4+, even in acidic solutions[68, 69].

Page 26 of 51
The use of 3,4,3-LI(1,2-HOPO) in the aqueous phase yields the total sequestration of the

tetravalent ions (e.g., Th4+, Pu4+ or Bk4+) and therefore decouples their extraction behavior from

that of the other cations. If a regular extractant like HDEHP, TBP, or TODGA is used in

combination with 3,4,3-LI(1,2-HOPO), then the other cations can be extracted independently. This

yields highly effective separations with separation factors Cf3+/Bk4+, Ln3+/Pu4+, An3+/Pu4+ >10+8

after a single step. Since 3,4,3-LI(1,2-HOPO) prefers cations with high Lewis acidity, it has very

weak affinity for Ac3+ so that it also enables the purification of actinium under certain

circumstances by retaining the other trivalent ions as well as the tetravalent actinides, with

SFAc3+/M3+ >1000 and SFAc3+/M4+ >1,000,000. Moreover, the high selectivity of 3,4,3-LI(1,2-

HOPO) for tetravalent actinides also allows for the separation of uranium and plutonium in a

PUREX-like configuration [67] with separation factors UO22+/Pu4+ of ~5,000 and without the need

for reducing Pu4+ to Pu3+, as required in the regular PUREX process. Despite the appealing and

versatile performances of 3,4,3-LI(1,2-HOPO), it should be noted that the separations based on

this ligand are only suitable for high-value elements, where not recycling the chelator (because it

binds to the tetravalent ions so strongly that its recovery is arduous) does not impact the overall

economy of the process. Additionally, since the HOPO binding groups are also efficient at binding

Fe3+ (because HOPO chelators are part of the so-called siderophore family, i.e., ferric iron binders),

the abovementioned separation methods would be strongly impacted if iron is present in the

process.

In another recent example[70], Nelson et al. used another HOPO ligand, consisting of three 2,1-

HOPO units attached to a tripodal linker, which forms neutral complexes [REE(HOPO)3R] in

order to perform REE separations via direct precipitation from aqueous solutions. The ligand-

induced REE precipitation method exhibits separation factors similar to that of classic extractants

Page 27 of 51
such as HDEHP and Cyanex® 572. This kind of approach could pave the way for REE separation

processes that are free of organic solvent, but the scalability and economy of the method still needs

to be investigated. In a related effort, led by Schelter et al.[71, 72], a novel tripodal hydroxylaminato

ligand [{(2-tBuNO)C6H4CH2}3N]3- (called TriNOx3-), was also developed for REE separation by

selective precipitation in organic solvents. While this approach necessitates the use of organic

solvents like THF or benzene, it opens a potential new way for separating critical metals like the

REEs. Despite the use of toxic organic solvents, the precipitation method using TriNOx3- yields

high separation factors, up to 359 between Nd and Dy after a single step. Interestingly, the same

TriNOx3- chelator can also be used for REE separation under a magnetic field (Figure 10). Schelter

and co-workers observed[73] the preferential crystallization of heavy REE complex of TriNOx3- in

chloroform when a magnetic field is present. This led the authors to perform efficient separation

of light versus heavy REEs (SFDy/La ≈ 500) by using a simple permanent magnet like Fe14Nd2B

(typically providing a magnetic field of H = 1.1 to 1.3 Tesla) to selectively precipitate the heavy

REEs. While this kind of method is still in its infancy and not yet ready for industrialization, it

could lead to future disruptive separation methods that would represent a hybrid between a

precipitation process and a magnetic separation.

Page 28 of 51
Figure 10. A) Synthesis and speciation of [REE(TriNOx)] complexes recently developed by Schelter et al.
for the magnetic separation of REE complexes in solution.[73] B) Photographs of [Tm(TriNOx)] crystals
forming in the presence of a magnetic field, i.e., a Fe14Nd2B permanent magnet. C) Separation factor as a
function of heavy REE3+ free ion angular momentum, J, for La/RE(TriNOx) mixtures. Adapted with
permission from ref. [73] Copyright 2020 Wiley.

Ionic liquids.
The need for more efficient and selective systems to process leaching solution produced from low-

grade and polymetallic ores drives the development of new extractants. For instance, as already

mentioned above, new organophosphorus compounds were recently developed for the selective

recovery of uranium from phosphoric acid[48]. Over the past two decades, many teams investigated

the properties of ionic liquids (ILs) as an alternative to classical extractants for solvent extraction.

As a reminder, ionic liquids are molten salts, mostly with organic cations and inorganic anions,

exhibiting melting temperatures lower than 100 °C. Three reviews[74–76] have recently been

published on ILs and readers are invited to consult these studies for detailed information on ILs.

Among the various IL systems previously considered, many studies concern imidazolium,

pyridinium, pyrrolidinium, piperidinium, phosphonium, ammonium, and more recently triazolium

cations combined with various anions such as chloride, bromide, PF6-, BF4-,

bis(trifluoromethanesulfonyl)imide, etc.[77]. However, in spite of the strong interest from the

scientific community for ILs (Figure 1B), no industrial application has yet been implemented with

this class of extractants in liquid-liquid extraction. On one side, ILs appear to have peerless

physical characteristics such as low volatility, low melting point, and large electrochemical
Page 29 of 51
window, which, in theory, offers many new opportunities for hydrometallurgical processes. On

the other side, the high cost, high viscosity, often high water solubility, and possible toxicity of

ILs narrow down their application potential under industrial conditions. Of note, many researchers

claim the “green” properties and the low toxicity of ionic liquids whereas the lack of studies on

their toxicity and ecotoxicity do not allow any conclusion yet, especially since their eventual

toxicity can depend on both the choice of the anion and the size/functionality of the alkyl side

chains of the cation[78, 79]. The toxicity and environmental impact of ILs should also be considered

for their full life cycle, from their synthesis to eventual disposal or recycling.

Likewise, the thermal stability of ILs is highly dependent on the nature of the anion and cation

forming the ILs and therefore thermal stability should not be claimed as a general property of ILs.

For example, a comprehensive study for Cao and Mu[80] showed that the temperature at which ILs

start to decompose can decrease by more than 200˚C just by varying the anionic part of the ILs

(e.g. replacing PF6- by a chloride or acetate anion). The long-term stability of ILs, or lack thereof,

is also a major issue to resolve before they can eventually be employed in industrial processes.

Comprehensive studies by Wang et al.[81] and Xu et al.[82] revealed that degradation of ILs occurs

via many pathways, including hydrolysis, nucleophilic reactions, SN2 reactions, acid-base

reactions, Hofmann elimination, thermal degradation, and even radiolysis. Depending on the

targeted process conditions and materials to be treated, the reactivity of ILs can readily limits their

long-term stability and application potential. Furthermore, the current cost and high viscosity of

ILs hinder their implementation in solvent extraction processes and future progress will be needed

to render ILs compatible with applications at the industrial level. Nonetheless, the use of ILs in

small-scale electrometallurgy, to target high-value metals, could be a more appropriate application

in the short-term as ILs combine high electrochemical window and high ionic conductivity[83].

Page 30 of 51
Deep Eutectic Solvents.
More recently, Deep Eutectic Solvents (DES) emerged as a new class of solvents for

hydrometallurgical processes. DES refers to a mixture a hydrogen bond donor(s) such as urea, and

a hydrogen bond acceptor(s) such as choline chloride which has a lower melting point than the

melting points of the individual compounds[84, 85]. DES are generally liquid at <100 °C, and they

exhibit physicochemical properties similar to traditional ILs, while being far less expensive (~

2 €/kg) and potentially more eco-friendly[86, 87]. Moreover, DES have several other advantages

relative to ILs, such as their ease of preparation, and ease of production from relatively inexpensive

and commercially available starting materials. These solvents could be used in leaching processes

as extensive studies have already been reported on the solubility of metals in DES[88–90]. They

could also be used in electrometallurgy to refine, recover, or electroplate metals as they also exhibit

wide electrochemical window[88–93]. Furthermore, the recent synthesis of hydrophobic DES pave

the way to their use as organic solvent in liquid-liquid extraction processes[94–98].

Finally, both uses of DES in the leaching operation of ores or wastes and solvent extraction could

contribute to the development of a new non-aqueous chemistry for the extraction and the

purification of metals from raw materials. Such water-free processes in hydrometallurgy could be

especially advantageous in arid regions and could lead to a significant reduction of the water

consumption, which is often a major criticism against hydrometallurgical processes. For example,

the work of Tersehatov et al.[97] showed that certain DES have the ability to extract specific metals.

The authors investigated the liquid-liquid extraction of indium from hydrochloric and oxalic acid

media by quaternary ammonium- and menthol-based DES. This work demonstrated the ability of

these DES to extract indium(III) via an ion-pair formation mechanism. In particular, the DES

composed of DL-menthol and lauric acid extract indium(III) efficiently only from aqueous

solution with low acidity (pH ≈ 3), and indium(III) stripping can occur by using 0.1 M diethylene

Page 31 of 51
triamine pentaacetic acid. However, despite the recent keen interest for DES, this technology is

still relatively new (Figure 1B) and far from ready for use in industrial processes. Similar to ILs,

the thermal stability as well as long-term behavior of DES will have to be investigated in detail

before this technology can be ready for applications beyond the laboratory scale.

Microfluidic devices.
As a general trend, an effort is made worldwide to design safer and more efficient

hydrometallurgical processes with lower environmental impact. Within this context, a key

approach is the intensification of the processes. A typical example in solvent extraction is the

successive transitions from mixers-settlers to pulse columns and, more recently, to centrifuge

extractors. The leading idea behind these technological transitions is to obtain higher mass transfer

and smaller liquid-liquid contactors by increasing the surface/interface-to-volume ratios (Figure

11). A next technological leap is at reach with microfluidic and labs-on-chip devices.

Figure 11. Comparison of different microreactors and conventional reactors (specific interfacial area,
characteristic dimensions, and capacity ranges). From ref. [99], with permission. Copyright 2019 American
Chemical Society.

Page 32 of 51
Microfluidics refers to the manipulation of fluids at sub-millimeter scales, which exacerbates the

surface forces compared to the volume forces. It should be pointed out that at the sub-millimeter

scale (typically 1-100 m) the behaviors are still mostly controlled by classical physics based on

bulk solution chemistry, by opposition to what happens in nano-fluidics (typically 100 nm

nanochannels) where specific fluid dynamic phenomena mainly driven by surface chemistry are

predominant[100]. Nano-fluidics is not relevant for hydrometallurgy and is therefore beyond the

scope of the present article. Until now, most of the research dedicated to metal separation and

recovery from feed solutions in micro-fluidic devices has been focused on liquid-liquid

extraction[101–104], however a few pioneering studies have also tentatively explored other unit

operations of hydrometallurgy, such as precipitation[105].

The primary advantages of operating at the sub-millimeter scale in microfluidic devices is the high

surface-to-volume ratios that allow very fast heat and mass transfer, i.e., rapid liquid-liquid

extraction of the metal ions. Figure 12 compares the volumetric mass transfer coefficients in

different scaled contactors and unambiguously shows that the mass transfer rates in microflow

extractors are 2 or 3 orders of magnitude higher than those in common extractors[106]. In this regard,

Kurniawan et al. have reported[107] that complete Pb(II) extraction with N,N-

diethylaminocarbonylmethoxy p-tertoctylcalix[4]arene derivative (EATOC) from 1.0 M HNO3

was achieved in a droplet-based microfluidic reactor within 2 s, whereas 90 min are necessary to

reach the equilibrium in batch. Advantages offered by microflow extractors are numerous: precise

control of dispersion of one phase into the other one with subsequent well-characterized flow fields
[103, 104]
, easy on-line instrumentation to visualize flows and mass transfers (e.g., optical

microscopes /digital cameras[103, 104, 108], micro-Raman spectroscopy[109]), possible intensification

of liquid-liquid mass transfer by ultrasound irradiation[110], reliable acquisition of kinetics data

Page 33 of 51
otherwise difficult to obtain using the standard batch method[111, 112], and possible enhancement of

selectivity on a kinetic basis as a result of short residence times[113].

Figure 12. Volumetric mass transfer coefficients in different scaled contactors. A) Conventional liquid-
liquid contactors; B) microflow extractors. From Wang and Luo[106]. Copyright 2017, Elsevier.

Microfluidic reactors mostly exploit either stratified flows[114] or segmented flows (droplet or slug

flows)[115, 116] generated with different types of junctions including T-junction, Y-junction, cross-

shaped junction, cross flow T-junction, and concentric junction[104]. These regimes depend on the

relative flow rates of the two phases involved, their interaction at the interface and the wetting

behavior on the wall of the microchannel. It should be pointed out that a given microsystem

requires to be operated under specific hydrodynamic conditions to obtain/maintain appropriate

flows as illustrated in Figure 13. For the ratio of the flowrates of aqueous and organic phases

Page 34 of 51
(Qa/Qo) > 1.18, the droplets eventually coalesce, whereas for Qa/Qo < 0.35, no droplet are formed

and back flow is observed in the to-be-dispersed phase[115].

Figure 13. Domain of use (green area) of two T-junctions glass chips for the chemical system [Eu(III)] =
10−2 M/[HNO3] = 4 M / (Dimethyl dibutyl tetradecyl malonamide)] = 1 M in n-dodecane. Squared symbols:
Flow-rate couples reached within the T-junction chip with an extraction length of 27.8 cm. Triangular
symbols: flow-rate couples reached within the T-junction chip with an extraction length of 1.125 cm.
Reproduced with permission from ref. [115]. Copyright 2018 American Chemical Society.

In an attempt to expand the domain of application of microfluidic devices and increase the

intensification of the separation processes, it has recently been proposed to take advantages of

continuous flow membrane extraction with a 3D Printed Flat Sheet Supported Liquid Membrane
[117]
(FS-SLM) to separate the feed and stripping channels of a microfluidic reactor . The

performance of such a microfluidic device was evaluated by quantifying uranium transport across

a 15 v/v% tributyl phosphate (TBP) liquid membrane at flow rates between 5 and 60 μL/min. It

was observed that the full recovery can be achieved in less than 10 min. By reducing the flowrate

of the stripping solution, it was possible to increase the concentration in the sample. Several

authors have reported studies on the liquid-liquid extraction, and sometimes the stripping, of

metals in microfluidic devices. These studies clearly demonstrate that microfluidic reactors usually

provide more efficient and more rapid extraction. Such observations often encourage the authors

Page 35 of 51
to suggest the potential scale-up for applications at large scale, in particular in hydrometallurgy.

However, such a leap from laboratory to industrial scale remains challenging from various points

of view as discussed below.

The first point to consider for the potential implementation of microfluidics in industrial-scale

hydrometallurgy, or even for the relatively small-scale production or recycling of high added-value

metals (PGMs, REEs, Ta, radiometals, etc.) is that metals have to be recovered from volumes of

leach solutions in the range of tens to hundreds of cubic meters. This necessarily implies to increase

the overall output of the microfluidic devices to reach a total processing capacity compatible with

an industrial production level. In principle, this can be obtained by deploying multiple

microreactors in parallel or in stacks. However, the sheer number of microfluidic devices needed

to reach the production level of classic hydrometallurgical processes still prevents their

implementation in the industry. The adoption of microfluidics by industrials will likely starts with

the production of very high-value compounds or for analytical chemistry. For instance, Ahn et al.

reported the production of about 31 g/hour of a commercial drug by copper catalysis with a

numbering-up approach[118]. With the same approach, Darekar et al.[119] obtained a capacity of

about 10 L/hour for the extraction of uranium(VI) from 1 M HNO3 using 30% (v/v) tributyl

phosphate (TBP) in dodecane and 20 parallel microbore tubes. Such results are encouraging, but

the gap is still important to reach the throughput necessary for most metals produced via

hydrometallurgy.

Another challenging aspect of microfluidics is the implementation of counter-current flowsheets.

Indeed, most microreactors described in published studies are operated at co-current flows. In

contrast, counter-current extractions are commonly used in chemical engineering as a method to

increase the extraction efficiency. To overcome this difficulty, Kriel et al.[120] have proposed to

Page 36 of 51
assemble extraction chips in a counter-current circuit, but with co-current flow in each chip. More

recently, Xie et al.[121] have adopted an oscillating feedback microextractor to demonstrate how a

co-current microextractor can be turned into a high-throughput counter-current microextractor.

Here again, the transition between co-current to counter-current microreactors remains tantalizing

and is not ready for industrial-scale processes. Potentially, the implementation of Flat Sheet

Supported Liquid Membrane in microfluidic devices may allow for an easier operation in counter-

current mode[117]. In summary, microfluidic liquid-liquid extraction is a breakthrough technique

for the recovery and separation of metals from various solutions, with convincing applications in

the field of analysis, and possible implementation for on-line control of hydrometallurgical

processes. On the opposite, its implementation as core technology for the primary production or

recycling of metals is still challenging and further work is still needed for adoption of such

technique at the industrial level.

Toward more sustainable processes.

The past few decades have seen a strong push to develop more sustainable hydrometallurgical

processes, going from the use of less toxic chemicals to the advent of solvent-free solvent

extraction methods, or the incorporation of biotechnologies in metal extraction processes. For

example, the hydrometallurgy of niobium and tantalum is currently based on liquid-liquid

extraction processes that operate with highly toxic fluoride media as the aqueous phase (typically

HF or NH4F + HNO3) because Nb and Ta are insoluble in other mineral acids. The highly

flammable extractant methylisobutyl ketone (MIBK) is also the gold standard in the current

extraction processes for Nb and Ta, further increasing the environmental impact and operational

risks. An alternative liquid-liquid extraction method that is fluoride-free has recently been

proposed with notably the use of an alkaline solution as feed and an organic phase based on the

extractant Aliquat 336.[122–127] The alkaline route takes advantage of the formation of inorganic Nb

Page 37 of 51
and Ta polyoxometalate ions, HxNb6O19x-8 and HxTa6O19x-8, and offers a greener approach

contrasting with the harsh conditions of the current industrial processes.

Biomaterials could also be one solution for a more sustainable hydrometallurgy. Indeed, bio-based

processes allow greener reagent production routes (e.g., bio cultures) and enable recovering metals

from feedstocks that are too diluted to be economically processed via current hydrometallurgical

techniques like liquid-liquid extraction. While bioleaching has been used for decades for the

industrial-scale hydrometallurgy of copper, recent studies have showed promising results for the

broader use of biomaterials (i.e., biolixiviants, biosorbents, and bioextractants) in hydrometallurgy

and extended its potential applications to other metals. A remarkable recent example is the

development by Zhou et al. of a “super-uranyl-binding protein” (SUP) for extraction of uranium

from seawater[128]. This engineered protein has femtomolar affinity (Dissociation constant, Kd, of

7.4x10-15 M, at pH 8.9) for UO22+ and >10,000-fold selectivity over competing ions found in

seawater, Na+, Ca2+, Sr2+, VO2+, etc. Yuan et al. further modified the SUP protein to embed it into

spidroin fibers, yielding selective and effective extraction of uranium from seawater at a capacity

of ~12 mg U per g of sorbent[129].

Similarly, the tensions in the REE sector could eventually be appeased by emerging bio-

hydrometallurgical processes. Brewer et al.[130, 131]

. recently developed microbead based on

common and inoffensive microbes (Escherichia coli strain) that have been engineered to display

lanthanide binding tags (short peptides with metal-binding moieties), allowing the selective

recovery of REE from electronic waste (Figure 14). The use of biomaterials, like microbes,

presents the unique advantage of unlocking the biological machinery to produce solid adsorbents,

hence circumventing the tedious and non-sustainable production routes of the chemical

extractants.

Page 38 of 51
Figure 14. Biosorption process for REE extraction from secondary feedstocks such as electronic waste. A)
General process strategy. B) Breakthrough curve for Nd with and without microbe-decorated microbeads.
Adapted with permission from ref. [131]. Copyright 2019 American Chemical Society.

Even more recently, a natural protein that is particularly selective for REE, called “lanmodulin”

(short for lanthanide-modulated protein), has been discovered by Cotruvo and co-workers[132]. This

small protein (only 12 kDa) has three binding pockets with picomolar affinity for the trivalent REE

(Kd, of ~1x10-12 M, at pH 5.0) ions which is orders of magnitude stronger that any previously

known biomacromolecular REE chelator. Lanmodulin also sustains acidic conditions[133],

complexing the REE3+ ions down to pH ~2.5 which is similar or better than manmade chelators

like EDTA or DTPA. Additionally, lanmodulin exhibits exceptional selectivity for REE3+ ions

over most competing ions (including Ca2+, Cu2+, Co2+, Ni2+, Zn2+, Al3+,etc.) allowing its use for

the selective recovery of REE from electronic waste, or even from currently untapped sources like

coal by-products (Figure 15)[133]. Further development of this bio-based technology also recently

led to column separations of REEs from non-REEs impurities, separations of REEs from one

another, as well as the selective extraction of actinides for radiochemistry applications[41, 134, 135].

Page 39 of 51
Figure 15. A) Lanmodulin-based selective recovery of REEs from coal leachate (Lignite). The
concentration ratios between the initial lignite leachate solution and the filtrates are given. A ratio higher
than 1 corresponds to an enrichment of the metal by the protein lanmodulin. B) Representation of
lanmodulin (blue) bound to three REE ions (cyan). Adapted with permission from ref. [133]. Copyright 2020
American Chemical Society.

While bio-based technologies targeting critical metals like REE or uranium have only been

developed recently and contrast with current chemical-based processes, external constraints such

as the customer demand for more sustainable supply chains and fading natural resources will likely

lead to a growing adoption of bio-based methods by the hydrometallurgy industry. Somehow

similar to the microfluidic devices, the next challenge for the biohydrometallurgical methods will

be to scale-up processes to meet the production goals of the industry. However, the development

of new biohydrometallurgical methods for critical materials can build on the decades-long

experience in the bioleaching processes and also on industrial-scale bioprocesses non-related to

metal production. Hence, it seems likely that the adoption of biohydrometallurgical methods by

the mining industry will be faster than that of microfluidic methods.

Outlook
Metal extraction and purification methods have continuously evolved to higher purity products,

higher yields, and at a lower cost. However, decades of industrialization and growing consumption

with little recycling created a situation where hydrometallurgists will have to refocus their efforts

from concentrated natural resources to low-concentration deposits[136] or urban feedstocks[137] with

high variability (in terms of valuable content, physicochemical form, nature, quantity of impurities,

Page 40 of 51
etc.). The present and future generations of hydrometallurgists will also need to steer chemical-

intensive processes toward more sustainable ones[138, 139] since customers, brands, regulators, and

investors, are more and more receptive to the way metals are extracted and produced before they

enter the supply chain. Perhaps even more challenging is the question about the metals that will

become critical in the short and long terms.[140, 141] The recent innovative systems that emerged in

the literature, such as microfluidic devices, biomaterials, new metal-binding chelators, ionic

liquids, and deep eutectic solvents, could ease the difficulties related to our metal supply chains in

the future. However, it is clear that these technologies need to be matured before industrial entities

incorporate them in their business models. It is also evident that none of these solutions alone will

replace the current hydrometallurgical processes in the near future. We posit that to address the

challenges associated with the hydrometallurgical production of refined materials our best hope is

to adopt a multi-prong approach combining, better utilization of natural resources, more efficient

processes, substitution of critical metals by less critical ones (when possible), recycling, and a

more responsible product consumption. Finally, given the sprawling influence of purified metals

in our daily life, one could wonder if hydrometallurgy should be an integral part of the chemistry

curriculum like other chemistry disciplines (organic chemistry, physical chemistry, inorganic

chemistry, etc.). This last question remains open for debate.

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Acknowledgements
Lawrence Livermore National Laboratory is operated by Lawrence Livermore National Security,

LLC, for the U.S. Department of Energy, National Nuclear Security Administration under Contract

DE-AC52-07NA27344 (LLNL-JRNL- 830607).

Author Contributions
G.J-P.D., A.C., and G.C. carried out literature search, discussed ideas, and contributed to the

writing of the manuscript.

ORCID numbers
Gauthier J.-P. Deblonde 0000-0002-0825-8714

Alexandre Chagnes 0000-0002-4345-6812

Gérard Cote 0000-0002-6323-9487

Competing interests
The authors declare that there are no competing interests.

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