Green chemistry - Reviewing Solvents as a practical way to Green up a reaction.

Over the last weeks, I have introduced and discussed the metrics for Green Chemistry; in this article, I will discuss solvents to green up reactions.

Solvent replacement

Traditionally, most solvents used are volatile organic compounds(VOC).

We use these VOCs because:

• Solvates reagents so that they dissolve – easier to react homogeneous substances together.
• Facilitates collisions between reactants and reagents.
• Means of temperature control either to give more energy to molecules or to absorb heat during exothermic reactions.
• "Heat sink"

The US EPA reports that the annual amount of industrial waste produced is around 100 billion tons, translating to $5 billion worth of VOCs used annually. This has a severe environmental impact.

If VOC are so common, why are they bad?

• High explosion and fire risk.
• Some solvents are carcinogenic and cause health problems
• It is high-cost as most solvents end up as waste (some are recycled).
• Most are sourced from crude oil, which is non-renewable.
• Much money is spent on PPE and paperwork.

Given that you are already investing in an effect by carefully selecting the VOC to ensure it is inert to reaction conditions, why not ensure it is green on top of this?

We should eliminate these traditional solvents to ensure a more environmentally friendly approach. How do we do that?

Several options can be considered:

• Solvent-free reactions.
• Use of water as a solvent.
• Supercritical Fluids.
• Fluorous Solvents
• Ionic Liquids.

Solvent-free reactions

To make a solvent-free reaction successful, there are several things we need to overcome:

• Making the reactants homogeneous.
• High viscosity.

Unsuitable if the reaction relies on the solvent itself, e.g. Ester protection of an amino acid:

But we can exploit this and use excess reagent rather than employing a different solvent, essentially turning it into a solvent-free reaction.

So, how do we carry out solvent-free reactions?

Well, the best way is to use mechanical systems such as:

Why does this work?

• In a crystalline solid, Molecules are held by weak interactions between molecules (e.g.?hydrogen bonds, donor-acceptor, and van der Waals host-guest interactions).
• Energetic mixing of two molecular solids tends to rearrange these weak forces (breaking and forming of new interactions).

Packing effects in the molecular solid organize reactants into:

• Suitable position for reaction (controlled by the relative positions of the reactants in the solid)
• Reaction-cavity formation? (reactivity takes place in a constrained environment generated by the surrounding molecules)
• Solid-state reactions provide stereo-controlled access to molecules otherwise difficult or unattainable from solution.

Eutectic Melt:

What are the issues with scale-up?

• Exothermic reactions may create too much heat, and without a heat sink, a mismatch between the rate of heat evolution and the rate of heat removal may occur, leading to rapidly rising temperatures with little time for correction.
• Over-pressurisation due to violent boiling or rapid gas generation.
• Elevated temperatures may initiate secondary, more hazardous reactions or decompositions.
• We, therefore, need to have a greater understanding of the processes to safeguard and control them.
• This is particularly important when considering the scale-up of a reaction.
• It can be controlled in several ways, including using carefully selected amounts of catalyst (to control the reaction rate).

Water as a Solvent

In traditional chemistry, water was often not used in various organic reactions; however, more recent developments have shown it to be the perfect solvent.

Synthesis of paracetamol is carried out in water with heating.

High-temperature water – higher pressure but not yet supercritical (I will touch on that later).

The Role of High-Temperature( Water.

• Solvent or medium for rearrangements and decarboxylations.
• Participant in hydrolyses of nitriles and esters, hydration of carbon-carbon double and triple bonds.
• Doubles as a catalyst and medium for other reactions (H+ ).
• With the addition of microwave heating, it is helpful for molecular transformations.
• It lessens the requirement for added acid or base, which has obvious benefits for safe, economical processing and lowering effluent disposal costs.

High T H2O as a solvent for organic reactions

• As T increases, the dielectric constant decreases, and H2O becomes more like an organic solvent (less polarized – less able to hold a charge).
• As T increases, the ionisation constant increases

? , e.g. 10-14 at 25oC and 10-11.30 at 300 oC

? i.e. water is a stronger acid and base at elevated T.

• As T decreases, the product separates from water as the properties of the water change.
• Rapid heating and cooling reduce the thermal decomposition of both reactants and products.

Supercritical Fluids

Supercritical(sc) is a special fluids state with unique properties

Supercritical Fluid is not new; it was first used in 1822 by Baron Cagniard de LaTour using equipment developed by Denis Papin in 1680.

Kurt Zosel started using supercritical fluid in the 1960s to remove caffeine from coffee. In the 1990s, it was integral in replacing CFCs in key processes such as polymer production—polystyrene and Polymethylmethacrylate.???

Solvent properties of supercritical fluids

• A crucial aspect of carrying out reactions in supercritical carbon dioxide is solubility.
• Pure supercritical carbon dioxide is a relatively nonpolar solvent, but due to its large molecular quadrupole, it has some limited affinity with polar molecules.
• Modifiers (e.g., MeOH and ionic liquids) can often be added?to improve the solubility of polar molecules.
• Alternatively, when reactions involve more than one reagent, less polar reagents can, in effect, act as modifiers, enhancing the solubility of more polar reagents and avoiding the need to resort to additional co-solvents.
• Another approach widely used to enhance solubility in supercritical carbon dioxide is introducing fluorinated substituents, often onto a ligand or counterion for organometallic catalysis. However, the expense of reagents can be a limiting factor, necessitating recycling.

Advantages

• Relative Low cost
• Non-toxic
• Non-flammable
• Ease of separation from products
• Properties ‘tunable’ with pressure and temperature
• High miscibility with gases

Solvent replacement, higher reactivity, selectivity and less energy, and use of CO2 as a C-1 source

• Small molecular organic and organometallic transformations
• Polymerisations with CO2 as a monomer or as an inert polymerisation medium
• Metal extractions ? Drug delivery
• Extractions, e.g. caffeine and hops
• Metal impregnation and deposition...

There are also several practical advantages associated with the use of supercritical carbon dioxide as a solvent:

• Simple evaporation achieves product isolation to total dryness. This could prove particularly useful in the final steps of pharmaceutical syntheses, where even trace amounts of solvent residues are considered problematic.
• Two beneficial complementary routes to particle formation with SCFs and supercritical carbon dioxide are a remarkably rapid expansion of supercritical solutions (RESS) and supercritical anti-solvent precipitation (SASP).

Limitations

• Dense phase CO2 has low dielectric constants and exhibits solvent features similar to conventional nonpolar solvents,?e.g., hexane. However, it can be overcome using co-solvents, e.g., alcohols, water, ionic liquids, and surfactants.

Technology for scCO2 work is commercially available, including stirred batch reactors with sampling capabilities. In situ characterisation methods have been developed: FT-IR, NMR, UV-vis, and laser flash photolysis.

Most promising reactions:

• Work well in non-polar solvents,
• Solvent sensitive,
• Small plant possibilities (￡),
• Reagents are not soluble in conventional solvents.

• One of the main differences between supercritical fluids and conventional solvents is their compressibility.
• Conventional solvents in the liquid phase require immense pressures to change density, whereas, for supercritical fluids, very significant changes in density and, hence, solvating properties can be achieved by comparatively small pressure and/or temperature changes, particularly around the critical point.
• This provides an infinite range of solvent properties, which can sometimes be tuned to significantly affect a reaction's outcome.
• Note that, in general, supercritical fluids are considerably less dense than conventional solvents. This can lead to solubility problems in some cases, but it also means they are substantially less viscous than traditional solvents, leading to significantly greater diffusivity. If diffusion is rate-limiting, this can result in considerably faster reaction rates.

Ionic Liquids

Like supercritical fluids, ionic liquids aren't new; being first discovered in 1911 by Waldens, it wasn't until 1951 that they received interest in being researched. However, at this point, the focus was more on electrolyte use. In the 80s and 90s, the use as an alternative for solvent was looked into.

So, what are Ionic liquids?

Ionic liquids(IL) are salts with a melting point below 100°C.

Other Characteristic:

• Negligible vapour pressure - high columbic forces, do not evaporate and are easy to contain, unlike volatile organic solvents.
• Thermal stability—varied, but some exceed 300oC. However, this is time-limited as some ILs decompose when kept at higher temperatures.
• High ionic conductivity.
• Large electrochemical window.
• Solvate organic, inorganic, and organometallic compounds, which can be used in metal catalyst reactions.
• Scope for changing the cation and/or anion to tailor properties, e.g. moisture stability, viscosity, acidity, miscibility with other solvents…..
• Polarity – as salts, they are expected to be polar.? Imidazolium ionic liquids are much less polar than water.? Polarity can change dramatically with the anion for some ILs.?

A slight detour into Melting Point chemistry.

• The ions forming ionic liquids do not pack well.
• Inadequate packing = liquid at lower temperatures.

The main factors:

• A good distribution of charge.? The best charge distribution is obtained for aromatic compounds.
• An unsymmetric structure.? This will limit the packing of the ions.? Use long alkyl chains.
• Weak intermolecular interactions. Intermolecular interactions such as hydrogen bonding should be avoided, as this will lead to a more compact structure and, thus, an increased melting point.?
• Large symmetric anions.? These will be well separated from the cation.

Toxicity and Environmental Issues

• Due to negligible vapour pressure, they cannot evaporate and pollute the atmosphere. This allows for extraction by distillation rather than using solvents.
• It can dissolve catalysts, which will remain in the IL so the whole thing can be recycled.
• It can be specifically designed to accomplish environmental tasks, such as extracting toxic heavy metal ions and Sulphur-containing compounds from petroleum products (S leads to SO2, which leads to acid rain).

BUT:

• The toxicity of many ILs is unknown as they are still relatively new.? Those studied have been found to have low toxicity, although this increases with increasing alkyl chain length.
• The PF6 anion undergoes hydrolysis to give HF and POF3, which are dangerous. This limits its use in industrial processes, as these chemicals can eat through glassware and reactors.

Other key points

• Presumed green due to negligible vapour pressure
• It does not consider how green the ionic liquid preparation is itself.
• Ionic liquids can be designed to possess properties such as toxicity, explosivity, non-biodegradability, etc., so they are not inherently green.
• “..the term ‘green’ should only be applied to an ionic liquid if both the ionic liquid and the process used to produce it are green, i.e. if all twelve principles of green chemistry apply.” (Green Chem., 2010, 12, 17-30)
• Note that the greenness of a process carried out at a laboratory scale will not necessarily be the same when carried out on an industrial scale. For example, Conventional heating is more energy efficient on an industrial scale than microwave heating, but the converse is valid on a laboratory scale.

Given IL's ability to help recycle catalysts and reaction products, we can examine product Separation.

Separation of Products

• It may be difficult to remove the product from the reaction media, e.g. DMF
• Requires many solvents for recrystallization and extraction.
• Using solvents uses up a finite resource, reduces the E-factor of an experiment, and costs companies millions for waste disposal.
• Environmental impact.

This ties into the fact that you can have the most selective, atom-efficient process in the world, but if the product cannot be separated from the reagents and catalysts, then it is useless!

Liquid-Liquid Biphasic Chemistry

This is one of the most promising approaches for separating liquid products from soluble reagents and catalysts.

Generally, the reagents and catalyst phase should be non-polar if the product phase is polar.

Hildebrand Solubility Parameter (δ)

• Provides a numerical estimate of the degree of interaction between materials.
• Can predict what solvent particular reagents will be soluble in.
• This will indicate which solvents are miscible, as solvents with similar (δ) are likely to be soluble in each other.
• The following equation calculates it:

Generally:

Although reagents and catalysts soluble in water and ionic liquids can be used for the synthesis and separation of products with lower polarity, the most non-polar media for biphasic systems are:

Fluorous Solvents

Solvents containing fluorine with a relatively large component in molecules are called fluorous solvents.

Properties of Fluorous Solvents

• Hydrophobicity
• Non-toxicity
• High oxygen solubility ( very good for reactions in which oxygen needs to be dissolved, such as the selective oxidation of methane to methanol, as it will easily dissolve oxygen but is exceptionally resistant to oxidation!).
• Inertness
• High thermal stability
• Non-flammability

?Efficient heat-transfer capacity

But:

• Although they are inert to atmospheric OH, O and H radicals and atoms, it is possible for them to be broken down by photolysis with light at a wavelength <130nm.
• CF4 and C2F6 released have a high global warming potential.
• Fluorocarbons are currently going through numerous environmental and safety reviews over claims they are bad.

How does it work in a biphasic system?

• They are miscible with some organic solvents on heating—at room temperature, they will form two phases, but on heating, they become homogeneous.
• Phase differences at lower temperatures can be exploited to separate products, recycle catalysts or both!

Tailoring the reaction

It is possible to make the reagents and catalysts soluble in fluorous media by adding fluorocarbon moieties to ligands:

• Typically, linear or branched perfluoroalkyl chains
• Want a high carbon number but not so high that they become harmful
• It may contain other heteroatoms which may aid solubility
• Are called “fluorous ponytails”

But:

Due to the electron-withdrawing effects of the many fluorine atoms, it may be necessary to insert an ‘insulating’ group to prevent the reagents or catalyst from having an altered reactivity.? These are typically hydrocarbon spacers.

• It is possible that when the reaction mixture is cooled to room temperature, due to the change in properties of the solvents, the product will precipitate out.
• May need to cleave the ‘fluorous ponytails’ from the products first so that they transfer to the non-fluorous phase.
• Can use Fluorous Reverse Phase (FRP) chromatography.

They are used in many industries, but they are often costly and might need to be more cost-effective in the scale-up. However, it is a typical cost of chemicals vs the cost of disposal. The change in laws also needs to be factored in.

In research, fluorous solvents are used to replace SCfluids as they have similar δ values, and you don't need the energy and safety needed to carry out the SCfluids test.

Summary

Moving toward greener solvents is a major way to reduce a reaction pathway's overall environmental impact. They can also reduce waste, improve separation, and increase product purity and yield. However, like everything in the world of sustainability, it is more of a greener vs green. The solvents discussed here are just the tip of the iceberg; many others are in development, plus a combination of them.

For industry, moving towards greener solvents doesn't just help with environmental label claims but can also reduce the need for expensive waste disposal and lower costs. It can also make processes more efficient and things more cost-efficient.

In the next article, I look at the catalyst as a way to reduce energy and waste.