Introduction

Metallaphotoredox catalysis combines photoredox processes with transition-metal catalysis. After absorbing visible light, the photocatalyst participates in single-electron transfer, generating radicals that subsequently enter bond-forming processes catalyzed by transition metals such as nickel. These reactions can enable bond constructions that are difficult to achieve using conventional methods under relatively mild temperature conditions, and therefore have potential applications in green chemistry.

Solvents remain an integral component of these reactions. In 2024, Joseph Bohlke and co-workers at Pfizer reported a study on sustainable solvents in metallaphotoredox catalysis in ACS Sustainable Chemistry & Engineering. Using decarboxylative arylation and cross-electrophile coupling as two representative reactions, they re-evaluated photocatalysts, solvents, and continuous-processing conditions.[1]

Alternative conditions using isopropyl acetate (IPAc) and acetone as the respective reaction media were identified. These results raise a key question in practical process development:

Solvent guides can be used to screen candidate solvents with more favorable health, safety, and environmental profiles, but whether a candidate solvent can actually replace the original solvent also depends on its chemical compatibility with the specific reaction and its process operability.

1. Why Can Solvent Replacement Change Reaction Outcomes?

1.1 Metallaphotoredox Reactions Involve Multiple Interconnected Processes

Taking the decarboxylative arylation reported by MacMillan, Doyle, and co-workers in 2014 as an example, carboxylic acids and aryl halides can form new C(sp³)—C(sp²) bonds under photoredox/nickel dual-catalytic conditions.[4]

With particular relevance to the role of solvents discussed in this article, this reaction can be summarized as two interconnected processes.

Photocatalytic generation of carbon-centered radicals:

After absorbing a photon, the photocatalyst enters an excited state. The carboxylic acid is converted into a carboxylate under the action of a base, and the carboxylate subsequently undergoes single-electron transfer (SET) with the excited-state photocatalyst: the carboxylate loses one electron to form a carboxyl radical, while the photocatalyst is converted into its one-electron-reduced state. The original study identified this photoinduced oxidation process as a key step in carbon-centered radical formation.[4]

This process can be simplified as:

Photocatalyst + photon → excited-state photocatalyst

RCO₂⁻ + excited-state photocatalyst → RCO₂• + one-electron-reduced photocatalyst

The resulting carboxyl radical RCO₂• then eliminates carbon dioxide to form a carbon-centered radical R•:

RCO₂• → R• + CO₂

Here, RCO₂⁻ represents the carboxylate, RCO₂• represents the carboxyl radical, and R• represents the carbon-centered radical formed after decarboxylation.

Nickel catalysis completes C—C bond formation:

The aryl halide Ar—X enters the nickel catalytic process; the carbon-centered radical R• generated through photocatalysis converges with the nickel catalytic process, ultimately forming the coupled product Ar—R.[4] The original study described the photocatalytic cycle and the nickel catalytic cycle as two coupled catalytic processes.

This process can be simplified as:

Ar—X + R• → nickel-catalyzed bond-forming process → Ar—R

The formation of products in this type of reaction involves interconnected steps including photoexcitation, single-electron transfer, radical generation, and nickel-catalyzed bond formation. The reaction also involves a range of chemical species, including carboxylates, bases, halide ions, photocatalysts in different electronic states, nickel complexes, and radicals.

All of these species are present in the same reaction medium. When the solvent is changed, dissolution and solvation, ionic states, photoinduced electron transfer, and the chemical environment surrounding nickel catalytic species may also change. This provides the chemical basis for the relatively high sensitivity of metallaphotoredox reactions to solvent selection.

1.2 Solvents Affect More Than Solubility

In metallaphotoredox reactions, solvents are involved in at least four categories of effects that may influence reaction outcomes.

Among these effects, photocatalysts can respond directly to changes in the solvent environment.

For example, for the organic photocatalyst 2,4,6-tris(9H-carbazol-9-yl)-5-chloroisophthalonitrile (3CzClIPN) used in the Pfizer study, femtosecond broadband transient absorption studies have shown that the spectroscopic behavior of its intramolecular charge-transfer excited state changes with the solvent environment.[6]

This means that absorption of light of the same wavelength by a photocatalyst does not necessarily imply that the subsequent excited-state relaxation and electron-transfer processes will be identical in all solvents.

For nickel-catalyzed processes, solvents with coordinating ability may also participate in coordination equilibria around the nickel center. The actual extent of these effects depends on the nickel source, ligand, substrate, and solvent composition. Therefore, the final reaction outcome cannot be predicted from a single parameter such as polarity, dielectric constant, or boiling point.

1.3 Yield Reflects the Outcome of Competition Among Multiple Reaction Pathways

The desired products of metallaphotoredox reactions are generally formed through multiple consecutive steps. Therefore, a solvent that favors one particular step does not necessarily increase the overall reaction yield.

For example, after a carbon-centered radical is formed, it must enter the nickel-catalyzed bond-forming process. At the same time, competing reactions may occur within the system, including radical hydrogen-atom transfer, reduction, and substrate dehalogenation. Formation of the desired product depends on:

Rate of radical generation → rate of radical capture and conversion by the nickel catalytic system → competition between desired bond formation and side reactions

If a solvent changes the rate of one of these steps or the state of the species involved, it will also alter the relative rates of different pathways throughout the reaction network.

The experimentally observed conversion, selectivity, and yield are therefore the combined results of multiple reaction steps.

2. Why Did Pfizer’s Two Model Reactions Lead to Different Solvent Choices?

Both reactions investigated by Pfizer involve metallaphotoredox dual catalysis, but they differ in their modes of radical generation, ionic composition, and reaction byproducts.[1]

2.1 Decarboxylative Arylation: 4CzIPN and IPAc

Decarboxylative arylation uses a carboxylic acid as the radical precursor.

After re-screening photocatalysts, Pfizer selected the organic photocatalyst 2,4,5,6-tetrakis(9H-carbazol-9-yl)isophthalonitrile (4CzIPN), and further evaluated reaction media suitable for process development, ultimately using IPAc under the optimized conditions.[1]

Several interrelated requirements are involved in this reaction:

① The carboxylic acid must form a carboxylate capable of undergoing single-electron oxidation;

② The photocatalyst must undergo effective photoexcitation and electron transfer;

③ The carbon-centered radical generated by decarboxylation must enter the nickel-catalyzed bond-forming process;

④ The nickel catalyst, base, and generated salts must remain in appropriate reaction states.

The authors also investigated light intensity and reaction time, and controlled the formation of dehalogenated byproducts by adjusting the irradiation conditions.[1]

The use of IPAc does not simply involve replacing the name of one solvent with another. The solvent, photocatalyst, and irradiation conditions collectively determine how the individual processes are matched under the reaction conditions.

2.2 Cross-Electrophile Coupling: the 3CzClIPN Organic Photocatalyst and Acetone

The second model reaction investigated by Pfizer was a cross-electrophile coupling between an alkyl bromide and an aryl bromide.[1]

This type of reaction can be traced back to a photoredox/nickel dual-catalytic method reported by the MacMillan group in 2016. The method uses tris(trimethylsilyl)silane (TTMSS) in the generation of alkyl radicals.[5]

The key radical-generation process can be simplified as:

Br⁻ → photooxidation → Br•

Br• + TTMSS—H → TTMSS•

TTMSS• + R—Br → TTMSS—Br + R•

First, bromide is photooxidized to form a bromine radical. The bromine radical abstracts a hydrogen atom from TTMSS, generating the silyl radical TTMSS•. The silyl radical then abstracts a bromine atom from the alkyl bromide R—Br. This process is referred to as halogen-atom transfer (XAT), and it generates the alkyl radical R•.[5]

The resulting alkyl radical subsequently enters the nickel-catalyzed bond-forming process and forms a new C(sp³)—C(sp²) bond with the aryl fragment derived from the aryl bromide. Optimization of the original method employed 1,2-dimethoxyethane (DME) as the reaction solvent and included screening of reaction parameters such as the base.[5]

Pfizer subsequently re-screened photocatalysts and solvents for this type of cross-electrophile coupling. In the model system, 2,4,6-tris(9H-carbazol-9-yl)-5-chloroisophthalonitrile (3CzClIPN) was used as the organic photocatalyst, with acetone as the reaction medium.[1] 3CzClIPN belongs to the class of carbazole-substituted dicyanoarene organic photocatalysts.

The conditions used for Pfizer’s two model reactions can be summarized as follows:

The two reactions differ in their radical precursors, mechanisms of radical formation, and overall reaction-system compositions, resulting in different solvent requirements. Good reaction performance of a solvent in one metallaphotoredox reaction cannot be used directly to conclude that the same solvent will be suitable for another reaction.

3. Why Is a Good Small-Scale Yield Still Insufficient to Establish Successful Solvent Replacement?

Solvent screening initially focuses on conversion, yield, and selectivity. These data indicate whether the chemical reaction can proceed effectively.

Once process development begins, the physical state of the entire reaction mixture throughout the reaction must also be evaluated.

3.1 A Reaction Mixture Is Not a Solution of Fixed Composition

Even if a homogeneous system can be formed at the beginning of a reaction, the following may still be generated as the reaction proceeds:

① Inorganic or organic salts;

② Reaction byproducts with low solubility;

③ Catalyst-related solids;

④ Materials that gradually precipitate as the composition changes.

Therefore, the same solvent must also meet another set of requirements:

Pfizer further evaluated the optimized decarboxylative arylation conditions in a small continuous stirred-tank reactor (CSTR).[1] In addition, an earlier continuous-flow study of this type of cross-electrophile coupling found that 2,6-lutidinium bromide could accumulate in the flow reactor and cause clogging.[7]

These observations show that good reaction yields in small vials demonstrate chemical feasibility, whereas continuous operation additionally requires validation of phase behavior, transport, and equipment operability.

3.2 Photochemical Reactions Are Also Subject to Light-Transmission Limitations

Photochemical processes require the photocatalyst in the reaction mixture to actually receive photons.

As reaction scale, concentration, and phase behavior change, the absorption and scattering of light by the reaction medium, as well as the effective optical path length, may also change. In addition to potentially affecting material transport, solid precipitation can alter the propagation of light through the reaction system.

Continuous-flow photochemistry studies have shown that when transferring reactions from microscale batch experiments to flow reactors, the light source, residence time, reactor configuration, and mass-transfer conditions must all be rematched. For silyl-radical-mediated cross-electrophile coupling, continuous-flow conditions can be re-optimized using dedicated high-throughput screening.[7]

Solvent evaluation in metallaphotoredox reactions therefore involves two categories of questions:

Chemical question: Can the reaction network operate effectively?

Engineering question: Can the reaction mixture operate stably in practical equipment?

Together, these two assessments determine the process suitability of a candidate solvent.

4. What Information Can Solvent Guides and ICH Classifications Provide?

4.1 Solvent Guides Are Used to Screen Candidates

The CHEM21 solvent guide evaluates conventional and emerging solvents based on safety, health, and environmental (SH&E) criteria and assigns classifications such as recommended, problematic, or highly hazardous.[2]

Such guides can narrow the range of solvents requiring experimental screening and help researchers prioritize solvents with more favorable properties.

Conversion, selectivity, catalyst stability, and phase behavior in a specific reaction must still be determined experimentally.

4.2 ICH Q3C Evaluates the Risks of Residual Solvents in Pharmaceuticals

Pharmaceutical processes also refer to the Q3C guideline for residual solvents issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

According to ICH Q3C(R9), the major solvents discussed in this article are classified as follows:[3]

ICH defines Class 2 solvents as residual solvents that should be limited because of their inherent toxicity, while Class 3 solvents have low toxic potential. The purpose of Q3C is to control residual solvents in pharmaceutical products and the associated risks of patient exposure.[3]

Class 3 reflects only the toxicological risk dimension of residual solvents and does not represent a complete assessment of process sustainability.

Process sustainability also involves factors such as the actual quantity of solvent used, reaction concentration, extraction and washing, solvent recovery, waste streams, and energy consumption.

5. How Should a Candidate Green Solvent Be Evaluated?

Based on the Pfizer study, the solvent replacement process can be summarized into four sequential levels.

These four stages follow a clear sequence.

Solvent guides first narrow the range of candidates; experimental screening then confirms whether the catalytic reaction is compatible with a candidate solvent; process experiments evaluate the behavior of the reaction mixture under practical operating conditions; finally, the overall impact of the replacement is assessed in the context of the entire process.

6. Classification Table of Representative Chemicals Related to Green Solvent Replacement and Metallaphotoredox Catalysis

Table 1. Reaction Solvents and Acid/Base Adjustment Reagents

Table 2. Photocatalysts, Nickel Catalysts, and Ligands

Table 3. Decarboxylative Radical Precursors, Coupling Substrates, and Radical Activation Reagents

Note: The products listed above are representative Aladdin products relevant to scientific research. Their specific applications should be determined in conjunction with product specifications, batch COAs, and the target reaction or evaluation system. Additional information on product specifications, grades, and COAs can be found on the Aladdin website by searching by “product name/CAS/catalog number.”

References

[1] Bohlke, J.; Armstrong, C.; Knauber, T.; González-Esguevillas, M.; Fernández, D. F. Sustainable Solvents in Metallaphotoredox Catalysis. ACS Sustainable Chemistry & Engineering, 2024, 12, 8998–9002. DOI: 10.1021/acssuschemeng.4c03003.

[2] Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. CHEM21 Selection Guide of Classical- and Less Classical-Solvents. Green Chemistry, 2016, 18, 288–296. DOI: 10.1039/C5GC01008J.

[3] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH Q3C(R9): Impurities: Guideline for Residual Solvents. Step 4, 24 January 2024.

[4] Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. C. Merging Photoredox with Nickel Catalysis: Coupling of α-Carboxyl sp³-Carbons with Aryl Halides. Science, 2014, 345, 437–440. DOI: 10.1126/science.1255525.

[5] Zhang, P.; Le, C. C.; MacMillan, D. W. C. Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electrophile Coupling. Journal of the American Chemical Society, 2016, 138, 8084–8087. DOI: 10.1021/jacs.6b04818.

[6] Zheng, R.; Cheng, M.; Ma, R.; Schipper, D.; Pichugin, K.; Sciaini, G. Solvent Effects on the Intramolecular Charge Transfer Excited State of 3CzClIPN: A Broadband Transient Absorption Study. Physical Chemistry Chemical Physics, 2024, 26, 1039–1045. DOI: 10.1039/D3CP04975B.

[7] González-Esguevillas, M.; Fernández, D. F.; Rincón, J. A.; Barberis, M.; de Frutos, O.; Mateos, C.; García-Cerrada, S.; Agejas, J.; MacMillan, D. W. C. Rapid Optimization of Photoredox Reactions for Continuous-Flow Systems Using Microscale Batch Technology. ACS Central Science, 2021, 7, 1126–1134. DOI: 10.1021/acscentsci.1c00303.

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