Photocatalysis is an innovative technique that harnesses light energy to drive chemical reactions by using photocatalysts, which can be activated by visible light rather than UV light, as is common in traditional photochemistry. Photocatalysis has generated great interest as a sustainable, practical means for organic synthesis through novel pathways.
This white paper presents examples from recent peer-reviewed research that show how the in-depth information and precise control provided by METTLER TOLEDO technologies aid in supporting green and sustainable chemistry across four thematic topics:
Photocatalysis is important for achieving chemical transformations using a clean, sustainable, renewable, non-hazardous energy source—visible light sourced from LEDs and solar radiation. Photocatalysis offers novel reaction routes and pathways that would be difficult to achieve using conventional synthetic methods. The transition metal oxides and complexes used as photocatalysts and photosensitizers can be sourced from earth-abundant, inexpensive metals such as titanium, iron, and zinc.
There are numerous existing and potential applications of photocatalytic processes in polymer, fine chemical, pharmaceutical synthesis, and environmental remediation. Oxidation, dehydrogenation, and hydrogen transfer are common synthesis processes accessible using photocatalysts. Photocatalytic-based syntheses have excellent chemoselectivity, even with numerous, varied functional groups in complex molecules. With respect to environmental applications, TiO2 nanoparticle photocatalysts are used for water treatment to eliminate pollutants and remove harmful gases from the atmosphere. Significant research efforts are underway using photocatalytic semiconductors for water splitting to produce hydrogen in clean energy applications.
EasyMax™ automated lab reactors control of key variables and reaction conditions is important in all catalytic processes. EasyMax's precisely controlled temperature and mixing capabilities ensure consistent photocatalysis outcomes and performance. EasyMax systems have a viewing window to observe the reaction vessel as the reaction proceeds. A visible light source situated near the window can induce photocatalysis in the reaction without negatively affecting vessel temperature control.
ReactIR™ and ReactRaman™ can track and analyze photocatalytic chemistry in real-time, directly in the reaction vessel. These methods provide key information about reaction kinetics, catalytic mechanisms, and catalytic cycles. When used in concert with EasyMax systems, this combination of technologies forms an ideal platform for developing photocatalytic processes.
Singh, S., Chakrabortty, G., & Roy, S. R. (2023). Skeletal rearrangement through photocatalytic denitrogenation: access to C-3 aminoquinolin-2(1H)-ones. Chemical Science, 14(44), 12541–12547. https://doi.org/10.1039/d3sc04447e
The authors comment that adding an amine group on an N-heteroaromatic ring is challenging yet very important in manufacturing small-molecule APIs. This work presents a novel approach for regioselective C-amination of quinoline-2(1H)-one that uses trimethylsilyl azide (TMSN3) in the presence of visible light to achieve the amination.
This approach is milder and more efficient than alternative methods since it does not use elevated temperatures or highly acidic conditions. They report that the reaction proceeds via cascade C–N bond formation and a denitrogenation process. In addition to amine addition to a wide range of 3-ylideneoxindoles, this method was also useful for synthesizing C-4 benzoyl/aryl substituted 3-aminoquinolin-2(1H)-one.
A series of experiments were performed to elucidate the reaction mechanism and to better understand the photocatalytic-induced modification of an identified triazoline intermediate that leads to the formation of the 3-aminated quinolin-2(1H)-one. This involved using ethyl (E)-2-(1-methyl-2- oxoindolin-3-ylidene)acetate (1a) as a model substrate and TMSN3 for the aminating agent. By tracking IR bands in real-time at 1201 cm⁻¹, 1317 cm⁻¹, and 1556 cm⁻¹ for the 1a substrate, triazoline intermediate, and product, respectively, ReactIR demonstrated rapid conversion of 1a to form the intermediate. This is evidenced by the decrease in the band at 1201 cm⁻¹ (substrate) and the increase band at 1317 cm⁻¹ (intermediate). This is followed by a decline in the band for the intermediate and a subsequent increase in the band for the product.
NMR analysis isolated the triazoline intermediate and confirmed its structure. The NMR results, in concert with the ReactIR measurements, clearly demonstrated the intermediate's role in the product's formation. Based on these experiments, the authors were able to propose a likely mechanism for the amination process.
Yetra, S. R., Schmitt, N., & Tambar, U. K. (2022). Catalytic photochemical enantioselective α-alkylation with pyridinium salts. Chemical Science, 14(3), 586–592. https://doi.org/10.1039/d2sc05654b
The authors commented that alkyl halides and sulfonates are frequently employed alkylating agents used in asymmetric catalysis for the enantioselective α-alkylation of enolates. Their interest was in developing a photochemical process for enantioselective alkylations that uses renewable and sustainable sources of alkylating reagents such as amino acid-derived substrates. Given the low electron acceptance capability of amino acid derivatives in enolate alkylations, the challenge was to develop a means to activate these compounds. Based on earlier work in the literature, the authors postulated that using amino acid-derived pyridinium salts as alkylating agents would be effective, given pyridinium salts are known to be used as radical precursors in enantioselective α-alkylations. They proposed that pyridinium salts form ground-state complexes with catalytically generated, electron-rich chiral enolate equivalents. In an extensive series of experiments, they showed that an electron-deficient Katritzky salt derived from the 2,2,2-trifluoroethyl ester of glycine reacted under conditions using a chiral amine catalyst, 2,6-lutidine, and 427 nm irradiation, provided the desired α-alkylation product.
Additional work showed that using a Lewis basic medium, such as dimethyl acetamide, improved yield (to 40%) and provided excellent enantiomeric excess (ee. 92%). Furthermore, using additives such as sodium iodide that improve ground-state complexation of the reaction components resulted in yields of 75% with 92% ee. Through in-depth mechanistic studies, they postulated that the catalytic enantioselective reaction may proceed simultaneously via an in-cage radical combination mechanism and a radical chain mechanism. The researchers went on to understand the photocatalytic reaction scope, including using the process in the total synthesis of the lignan natural products (−)-enterolactone and (−)-enterodiol.
A key observation in their work was the critical importance of controlling reaction temperature. Performing these reactions at room temperature negatively affected the enantioselectivity, and maintaining 92% ee required running the reaction at a temperature of 4 °C. Temperature control was challenging since the reaction was continually irradiated with a light source near the vessel. For this reason, the researchers used an EasyMax 102 system. In an article highlighting Professor Tambur’s work on catalytic photochemical enantioselective α-alkylation using pyridinium salts (Synform, 2023/06, A100-A105), he comments: “We finally purchased the EasyMax 102 Advanced Thermostat system from Mettler-Toledo AutoChem, Inc. This turned out to be the most important purchase for the success of the project. Although the EasyMax had never been used for photochemical reactions, we identified two key features of this instrument. First, it enables the maintenance of a constant low reaction temperature for long times. Second, the instrument has a clear window into the reaction chamber, which is typically used to view
into the reaction, but we identified this as an opportunity to shine light from a lamp at a controlled distance without impacting the reaction temperature. To our delight, the EasyMax provided a new level of consistency in our results.”
Dagar, N., Singh, S. and Roy, S.R. (2022). Synergistic Effect of Cerium in Dual Photoinduced Ligand-to-Metal Charge Transfer and Lewis Acid Catalysis: Diastereoselective Alkylation of Coumarins. J. Org. Chem. 87(14), 8970–8982. https://doi.org/10.1021/acs.joc.2c00677
The authors report developing a practical, straightforward method for C-4 alkylation of coumarin derivatives utilizing a photocatalytic process. The novel method uses readily available cerium in a dual role to generate an alkyl radical through a photoinduced ligand-to-metal charge transfer (LMCT) process and build stereospecific C–C bonds through Lewis acid catalysis using carboxylic acids as the alkylating source to effect the coumarin 3-carboxylates alkylation.
Extensive investigations were performed to understand the mechanism of this process. For example, a reaction performed using pivalic acid as the radical precursor with ethyl 3-coumarincarboxylate in the presence of CeCl3 and tBuOK under 427 nm irradiation led to excellent yields of the desired product. When this same reaction was performed in the presence of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), a radical scavenger, the reaction was inhibited, supporting the proposal that the reaction likely proceeds through a radical intermediate.
UV-Vis spectroscopy supported the proposed photoinduced ligand-to-metal charge transfer (LMCT) process. In the presence of the 427 cm⁻¹ light, changes in the absorption spectrum of the Ce (IV) Cl-alkoxidecomplexindicated that LCMT could be involved, generating Ce(III) and the alkyl radical by eliminating CO2. In-situ FTIR reaction progress studies did reveal and track the formation of CO2 at 2344 cm⁻¹ and a new C=C band at 1668 cm⁻¹ likely arising from an enolate-type intermediate. Cerium forms complexed with the intermediate as mentioned above, followed by diastereoselective protonation, resulting in product formation.
