Visible-light-promoted organic reactions can offer increased reactivity and selectivity via unique reaction pathways to address a multitude of practical synthetic problems, yet few practical solutions exist to employ these reactions for multikilogram production. We have developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high-intensity laser to drive photochemical reactions at unprecedented rates in continuous flow, achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses the Beer–Lambert law as a guideline to optimize catalyst concentration and reactor depth for maximum throughput. This laser CSTR platform coupled with the rationale for design can be applied to a breadth of photochemical reactions.

A pharmaceutical industry viewpoint on how the fundamental laws of photochemistry are used to identify the parameters required to implement photochemistry from lab to scale. Parameters such as photon stoichiometry and light intensity are highlighted within to inform future publications. Photochemistry employs photons to drive chemical transformations. Traditional approaches rely on the direct excitation of bonds with light 1,2. In contrast, photoredox catalysis uses a photosensitizer to facilitate electron transfer, generating reactive intermediates under mild conditions 3. From a pharmaceutical industry point-of-view, photochemistry is a powerful tool to access highenergy intermediates that can provide novel reactivity and enables new disconnections, allowing target-and diversity-oriented synthesis to be explored 4. Photochemistry is extensively used within medicinal chemistry projects, but has not yet been extensively employed for the commercial manufacture of pharmaceutical agents 5. The scientific community has published new and exciting photochemical methods, but in our experience these transformations can be challenging to reproduce 3,6. We believe that this difficulty results from an under-emphasized importance of fundamental photochemical concepts, which renders translation of methods between setups challenging. Most authors try to describe the key features of the photochemical system used in their experiments; however, the description may not be completely sufficient to ensure reproducibility in a different lab or comparable reactor system. It can be quite common to find little technical detail about the equipment setup in the Supplementary Information and many summaries fall short of fully characterizing the photo-physical properties of their setup. We believe that careful characterization and description of the photochemistry equipment is essential; more systematic and better documented experimentation will enable greater mechanistic understanding, leading to facile identification of the key scale-up factors. From a review of the fundamentals of photochemistry, we will detail the minimum information to include in any photochemistry-related publication. This will enable the chemistry community to more readily assess and adopt photochemical transformations. We will then look toward the future of photochemistry for a manufacturing system that applies this technology. Grotthuss-Draper law Light must be absorbed by a chemical substance for a photochemical reaction to occur. Photon absorption excites a molecule from its ground state to an excited state. Chemical substances only absorb at specific wavelengths, so it is critical that the right wavelength is selected for the desired transformation.

The kinetic and mechanistic understanding of cooperatively catalyzed aldol and nitroaldol condensations is probed using a series of mesoporous silicas functionalized with aminosilanes to provide bifunctional acid−base character. Mechanistically, a Hammett analysis is performed to determine the effects of electrondonating and electron-withdrawing groups of para-substituted benzaldehyde derivatives on the catalytic activity of each condensation reaction. This information is also used to discuss the validity of previously proposed catalytic mechanisms and to propose a revised mechanism with plausible reaction intermediates. For both reactions, electron-withdrawing groups increase the observed rates of reaction, though resonance effects play an important, yet subtle, role in the nitroaldol condensation, in which a pmethoxy electron-donating group is also able to stabilize the proposed carbocation intermediate. Additionally, activation energies and pre-exponential factors are calculated via the Arrhenius analysis of two catalysts with similar amine loadings: one catalyst had silanols available for cooperative interactions (acid−base catalysis), while the other was treated with a silanol-capping reagent to prevent such cooperativity (base-only catalysis). The values obtained for activation energies and pre-exponential factors in each reaction are discussed in the context of the proposed mechanisms and the importance of cooperative interactions in each reaction. The catalytic activity decreases for all reactions when the silanols are capped with trimethylsilyl groups, and higher temperatures are required to make accurate rate measurements, emphasizing the vital role the weakly acidic silanols play in the catalytic cycles. The results indicate that loss of acid sites is more detrimental to the catalytic activity of the aldol condensation than the nitroaldol condensation, as evidenced by the significant decrease in the pre-exponential factor for the aldol condensation when silanols are unavailable for cooperative interactions. Cooperative catalysis is evidenced by significant changes in the preexponential factor, rather than the activation energy for the aldol condensation.

a b s t r a c tWeak acids are known to enhance the activity of amines in aldol condensation reactions on silica-based catalysts. The effects of acid strength and arrangement of the promoting site with respect to a secondary amine have been investigated in the aldol condensation of 4-nitrobenzaldehyde with acetone. Changing the substituent of this secondary amine from a methyl to an ethyl group decreases the activity. An intramolecular OH function provided by a primary alcohol incorporated on the b-carbon of the amine substituent exhibits a similar cooperativity as an intermolecular OH function provided by neighboring surface silanols. A maximum activity was achieved when the secondary amine with the same primary alcohol-containing substituent was surrounded by surface silanols, indicating the potential advantage of simultaneously activating both reactants by the formation of a hydrogen bond in contrast to the consecutive activation when there is only one promoting site in the vicinity of the amine. Changing the alcohol to stronger acids resulted in a reduced cooperativity with increasing acid strength. After removing the silanols from the surface, the activity of the catalysts which exhibit an intramolecular cooperativity retained about 68-83% of their activities while the activity of the conventional secondary amine was reduced by a factor of four compared to its intermolecularly cooperative counterpart.

Molecular dynamics simulations are performed to investigate the cooperatively catalyzed aldol condensation between acetone and 4-nitrobenzaldehyde on alkylamine (or alkylenamine)-grafted silica surfaces, focusing on the mechanism of the catalytic activation of the acetone and 4-nitrobenzaldehyde by the acidic surface silanols followed by the nucleophilic attack of the basic amine functional group toward the activated reactant. From the analysis of the correlations between the catalytically active acid-base sites and reactants, it is concluded that the catalytic cooperativity of the acid-base pair can be affected by two factors: (1) the competition between the silanol and the amine (or enamine) to form a hydrogen bond with a reactant and (2) the flexibility of the alkylamine (or alkylenamine) backbone. Increasing the flexibility of the alkylamine facilitates the nucleophilic attack of the amine on the reactants. From the molecular dynamics simulations, it is found that C3 propylamine and C4 butylamine linkers exhibit the highest probability of reaction, which is consistent with the experimental observation that the activity of the aldol reaction on mesoporous silica depends on the length of alkylamine grafted on the silica surface. This simulation work serves as a pioneering study demonstrating how the molecular simulation approach can be successfully employed to investigate the cooperative catalytic activity of such bifunctional acid-base catalysts.