Sustainability in Organic Chemistry: Special Student/Post Doc Session

The non-proteinogenic amino acid Adda is a structurally complex and biologically essential residue found in cyanobacterial toxins such as microcystins and nodularins, where it plays a critical role in protein phosphatase inhibition and hepatotoxicity. Despite it is importance in environmental monitoring, toxicology, and chemical biology, the synthesis of Adda remains challenging due to its multiple stereocenters, sensitive functionality, and reliance on lengthy or resource-intensive synthetic routes.

Herein, we report a highly convergent and operationally efficient nine-step synthesis of Boc-Adda-OH featuring a key intermolecular Heck coupling between two advanced fragments. This strategy replaces traditional Wittig and organometallic cross-coupling approaches that often require toxic reagents, extensive step counts, and limited scalability. Notably, the Heck reaction proceeds with excellent regio- and stereoselectivity in the presence of a labile isoxazolidinone moiety, demonstrating for the first time that palladium-catalyzed Heck chemistry can be successfully employed without compromising sensitive N-O bonds.

The route benefits from high step economy, improved functional-group tolerance, and minimized protecting-group manipulations, aligning well with green chemistry principles such as waste reduction and process efficiency. Final N–O bond cleavage affords Boc-Adda-OH in high yield, providing rapid access to this key building block for downstream peptide synthesis.

This concise and scalable approach enables more sustainable access to Adda and related cyanobacterial peptide motifs, facilitating future studies in environmental toxicology, harmful algal bloom monitoring, and the synthesis of biologically relevant peptide analogues.

Directed radical C–H functionalization emerges as a powerful method of preparing complex molecules and bioactive motifs, addressing limitations of noble-metal usage, harsh conditions in pair-electron chemistry and excessive substrate loading in non-selective radical C–H activation. However, previous approaches were often limited to the usage of oxidative, unstable radical precursors prepared in multistep and/or reliance of expensive photocatalyst/additive, resulting in less functionality tolerance and economy. The development of a sustainable reaction manifold that can accommodate different classes of C(sp³)–H bonds (1^o, 2^o, 3^o), acyclic/cyclic scaffolds of carboxylic acids remain challenging. Here we report a general regioselective C(sp³)–H functionalization of carboxylic acids enabled by iron radical ligand transfer (RLT) to construct medicinally relevant C–O and C–N bonds. Problematic substrate classes (methylene C–H etc.) in organometallic activation or radical polar-crossover and C–H classes of diverse carboxylic acid scaffolds are all addressed. Critical to the success is the adoption of earth-abundant, multifunctional iron which not only serves as radical initiator in C–H abstraction, but also as radical sequester to deliver X-type ligand to transient alkyl radical through RLT. Preliminary mechanistic studies support a radical nature of this RLT platform, indicating a powerful mean of directed radical C–H functionalization of feedstock chemicals.

Within the constantly evolving fields of green chemistry, the use of nontraditional activation methods takes a central role. Their contribution works by relieving the necessity of harsher chemicals or conditions to initiate certain organic reactions. Friedel-Crafts alkylation/hydroxyalkylation is an electrophilic aromatic substitution that is one of the most important methods to create C−C bonds. It is instrumental in pharmaceutical, fine chemical and material chemistry industries, commonly relying on Lewis acid catalysts to be activated, generally aluminum chloride. In this work, hydroxyalkylation has been performed between various substituted pyrroles and trifluoroacetophenones under high hydrostatic pressure (HHP) without the use of solvent or catalyst.
In the optimized HHP reactions, yields up to 96% were obtained under 3.8 kbar of pressure compared to 5% yields observed at ambient pressure.
High hydrostatic pressure has shown to be an effective and green activation method for this reaction by removing the need for addition of the catalyst and its subsequent removal from the product mixture, as well as negating the need for solvent.

Diazotization is a key process in organic synthesis, enabling the conversion of primary aromatic amines into diazonium salts, which are important intermediates in, for example, the synthesis of azo dyes. Traditional diazotization methods utilize strong mineral acids (e.g., hydrochloric acid/HCl), which pose safety, corrosion, and environmental risks due to their toxicity and handling hazards. Furthermore, these mineral acids are typically used in stoichiometric or excess amounts, are not readily recoverable or reusable after reaction, and require neutralization, resulting in substantial acidic and salt waste. To promote green chemistry principles, this study examines the use of a monomeric form of alginic acid (AA), a renewable, biodegradable, and low-toxicity biopolymer derived from brown algae, as an eco-friendly alternative acid medium for diazotization reactions that can be potentially recycled for subsequent use.
Diazotization was carried out using aniline, 4-aminobenzenesulfonic acid, and other aromatic amines at both 0–5 °C and room temperature, followed by coupling with β-naphthol to produce various azo dyes. All seven dye systems successfully underwent diazotization under alginic acid conditions, with yields of 62–89% at 0–5 °C and 23–60% at room temperature. The recyclability and recovery of alginic acid were evaluated across all dye systems, with success observed for only C.I. Acid Orange 7 (6 reaction cycles). The stability of the diazonium salts derived from 4-methoxy aniline and 4-aminobenzene sulfonic acid was further evaluated at 30 min, 24 h, and 72 h, and the diazonium salts of 4-aminobenzene sulfonic acid showed high initial coupling efficiency and short-term stability up to 24 h, followed by rapid degradation between 24 h and 72 h. In contrast, (E)-1-((4-methoxyphenyl)diazenyl)naphthalen-2-ol, derived from the 4-methoxy aniline diazonium salt, showed lower initial yields but greater stability over time (up to 72 h), consistent with slower diazonium salt decomposition. These results indicate that alginic acid is a promising, safer, and more sustainable substitute for conventional mineral acids in diazotization, while highlighting the need for further work to optimize the process, evaluate scalability and environmental impact, and expand its applicability across diverse azo dye systems.

Mechanochemistry provides a sustainable alternative to solution-phase synthesis, yet solvent-free environments can enable reaction pathways inaccessible under conventional conditions. Here, we present a systematic experimental and computational study of nucleophilic substitution reactions under mechanochemical activation, focusing on the formation and selectivity of alkyl thiocyanates (R–SCN) and alkyl isothiocyanates (R–NCS). While aryl analogues have been previously prepared mechanochemically, alkyl variants and their stereochemical behavior have remained largely unexplored.
Using chiral benzylic halides as model substrates, we demonstrate that reaction outcome can be selectively tuned yielding either thiocyanate or isothiocyanate products depending on mechanochemical parameters. Product distribution and stereochemical outcomes are strongly influenced by counterion identity, temperature, milling time, and milling-vessel composition. Under certain conditions, classical stereoinvertive SN2 substitution dominates, whereas elevated temperatures and specific metal surfaces promote racemization and isomerization consistent with radical-mediated pathways. Radical inhibition experiments and variation of milling materials reveal a critical role of metal surfaces, particularly iron-containing vessels, in enabling these alternative pathways.
Density Functional Theory calculations support a concerted SN2 mechanism as the primary substitution route while highlighting the influence of cation–anion interactions on transition-state stabilization and selectivity. Deviations from classical solution behavior demonstrate that mechanochemical environments reshape substitution reactivity through ion pairing, surface effects, and mechanical activation.
These findings show that mechanochemistry is not only a greener synthetic platform but also a means to access unconventional substitution pathways, expanding mechanistic understanding and offering new strategies for selective solvent-free synthesis.

Achieving selective and general 1,2-diamination of aryl dihalides remains a major unsolved challenge in cross-coupling chemistry due to catalyst deactivation by ligand-like diamine products, competitive mono-amination, and hydrodehalogenation. We report a novel micellar strategy that overcomes these limitations and enables efficient palladium-catalyzed 1,2-diamination under sustainable, low-energy conditions. Our key innovation is the in situ generation of NaOtBu from inexpensive NaOH and t-BuOH within micellar nanoreactors, eliminating the need for costly, moisture-sensitive alkoxide bases. The lipophilic NaOtBu forms selectively inside the hydrophobic PS-750-M micelle core, where catalysis occurs—preventing the resulting 1,2-diamine products from occupying catalytic sites and suppressing de-ligandation events. This compartmentalization also minimizes unproductive hydrodehalogenation and enables low catalyst loadings, reduced temperatures, with water as the reaction medium. The method delivers a broad range of 1,2-diamines, including heteroaryl substrates and diverse amines, providing otherwise difficult-to-access scaffolds for NHC and anionic ligand development. Overall, this work introduces a combination of micellar catalysis and in situ base activation that directly addresses long-standing mechanistic barriers in diamination chemistry and establishes a greener, scalable, and resource-efficient platform for C–N bond formation. This work will also shed light on how traces of organic solvents can adversely impact this transformation.

The formation of C–C bonds via Grignard-type additions enabled access to complex molecules such as pharmaceuticals and agrochemicals. Yet traditional organometallic reagents mandate stoichiometric amounts of metals and are generally intolerant to moisture and air, producing copious waste and limiting their compatibility with one-pot chemoenzymatic process development. And although hydrazones as organometallic equivalents have recently emerged as a general and sustainable approach to bypass these challenges—by generating only water and nitrogen gas as benign by-products—it still presented critical areas for improvement to showcase its applicability as a greener alternative to classical methods. First being the use of scarce and precious metals and the second being the development of methods that are operationally simple, yet robust and highly tolerant to a wide diversity of conditions.

To address these, we developed a manganese-based catalyst system for the addition of aldehydes to carbonyl compounds and surrogates, producing secondary and tertiary alcohols with yields of up to 91%. By employing a robust and reproducible method under aqueous and aerobic conditions, we were then able to apply it in several sequential one-pot chemoenzymatic processes. In this talk, we will therefore not only discuss how we leveraged hydrazone umpolung to access a greener solvent and biocatalysis, but also how integrating enzymatic solutions contributed to our broader research projects.