Reactive intermediate | EPFL Graph Search

In chemistry, a reactive intermediate or an intermediate is a short-lived, high-energy, highly reactive molecule. When generated in a chemical reaction, it will quickly convert into a more stable molecule. Only in exceptional cases can these compounds be isolated and stored, e.g. low temperatures, matrix isolation. When their existence is indicated, reactive intermediates can help explain how a chemical reaction takes place. Most chemical reactions take more than one elementary step to complete, and a reactive intermediate is a high-energy, yet stable, product that exists only in one of the intermediate steps. The series of steps together make a reaction mechanism. A reactive intermediate differs from a reactant or product or a simple reaction intermediate only in that it cannot usually be isolated but is sometimes observable only through fast spectroscopic methods. It is stable in the sense that an elementary reaction forms the reactive intermediate and the elementary reaction in

Development of remote C-H bond functionalization of redox-active alcohol derivatives and oxidative transformations under photoredox catalysis

Alexandre Julien Florent Leclair

The development of radical-based remote C(sp3)-H functionalizations of redox-active alcohol derivatives, oxidative cycloaddition and rearrangement transformations under visible light photocatalysis constitute the basis of this thesis.The first chapter describes the exploration of several strategies to effect the Î²- and Î³-C(sp3)-H functionalization of alcohols under reductive conditions through the 1,5-hydrogen atom transfer of reactive radical intermediates. Two types of N-phthalimidoyl precursors were synthesized and used under metal and photoredox catalysis to effect a formal Î³-C(sp3)-H functionalization. The fragmentation of primary N-phthalimidoyl oxalates could be smoothly realized under photoredox catalysis. However, the generated alkoxycarbonyl radicals did not allow for a distal functionalization and instead could only be trapped by direct addition to electron-poor alkenes. More potent 1-alkoxy vinyl radical intermediates proved to be too unstable and no control of the fragmentation could be achieved. Two approaches were designed to pursue the Î²-C(sp3)-H functionalization of redox-active alcohols. An iron-catalyzed C-H azidation of N-acyloxy imidates was discovered and optimized to enable, after simple hydrolysis, the synthesis of valuable Î²-azido alcohols. N-phthalimidoyl carbonates were also investigated to this end, however the exceptional hydrogen abstracting properties of these electrophilic (alkoxycarbonyl)oxyl radicals could not be tempered and only decomposition to the parent alcohol was detected.The study of two photoredox catalyzed oxidative transformations is discussed in the second chapter. Building on the propensity of indoles to produce radical cation intermediates under photoinduced single electron oxidation, an innovative oxidative ring-expansion of 1-(indol-2-yl)cyclobutan-1-ols was developed. Under mild aerobic visible-light conditions, a series of 2,3,4,9-tetrahydro-1H-carbazol-1-ones were accessed with complete regioselectivity in the presence of a catalytic amount of mesityl acridinium salt. Gratifyingly, this reaction could be extended to benzo[b]thiophenes analogues. The synthetic potential of this transformation was demonstrated by achieving a total synthesis of (Â±)-uleine, using our methodology to furnish one of the key fragment. A series of experiments were performed to gain insights in the mechanism of this transformation. A complex cascade reaction was suggested, involving two successive oxidative 1,2-alkyl shifts and initiated by the formation of a radical cation. Next were started synthetic studies toward the total synthesis of (Â±)-decursivine, a moschamine-related indole alkaloid, with the aim of developing an intramolecular oxidative [3+2]-cycloaddition under photoredox catalysis. Several precursors were synthesized and attempted under a large variety of reaction conditions to effect the cycloaddition, unfortunately without success. At best, the dimerization of a transient phenolic radical was observed. Efforts to promote an intramolecular reaction remained unsuccessful.

EPFL2021

Copper-Catalyzed 1,2-Methoxy Methoxycarbonylation of Alkenes with Methyl Formate and Synthetic Studies Towards the Total Synthesis of Koumine, Voacafricine A and Voacafricine B

Balázs Budai

The development of an unusual oxidative alkene difunctionalization using methyl formate and syn-thetic studies towards alkaloid natural products provide the basis of the thesis. The first chapter details the development of a method that forges methoxycarbonyl radical direct-ly from its most accessible precursor: methyl formate. Although the aforementioned transfor-mation was documented in the literature, no synthetically useful method was developed at the time. We were able to identify conditions that transform methyl formate and simple styrene de-rivatives to value added ï¢-methoxy alkanoates and cinnamic acid derivatives under copper cataly-sis. We also demonstrated that by tethering nucleophilic moieties to the styrene substrates, we could access medicinally important heterocycles such as pyrrolidines, tetrahydrofurans and ï§-lactones. Our method proved to be scalable on each classes of substrates. Mechanistic studies re-vealed that methyl formate has an unprecedented double role in the transformation. It acts as a precursor for methoxycarbonyl radical; furthermore, it is the direct source of the ï¢-methoxy func-tion in the synthesis of ï¢-methoxy alkanoates. A ternary ï¢-diketiminato-Cu(I)-styrene complex, fully characterized by NMR spectroscopy and X-ray crystallographic analysis is capable of catalyz-ing the same transformation. We hypothesize that pre-coordination of electron-rich double bond to copper might play an important role in the polarity-mismatched addition between nucleophilic methoxycarbonyl radical and electron rich olefins. Synthetic studies toward the total synthesis of koumine is discussed in the second chapter. Our synthetic strategy features an oxidative ring closing, Fukuyama indole synthesis and an enantiose-lective Diels-Alder cycloaddition for the construction of the core of koumine skeleton. We designed a rapid route to access 1,2-dihydropyridine derivatives and these compounds were examined as dienes in the Diels-Alder cycloaddition reaction. Despite our efforts, we were unable to effect the [4+2] cycloaddition, which eventually lead us to decide to discontinue our campaign. In chapter three, our synthetic efforts toward voacafricine A and voacafricine B is presented. In our pursuit towards the natural products, we devised and followed a divergent and potentially en-antioselective strategy. We successfully developed a synthetic route to reach the key intermediate in five steps. Despite our efforts, we were not able to construct the remaining F ring of the natural product. Our conformational analysis of advanced intermediates suggest that epimerization of the C14 stereocenter potentially unlocks the desired reactivity and enables us to reach the target mol-ecules. Work towards the total synthesis of voacafricine A and voacafricine B is underway and may focus on the conformational manipulation of advanced intermediates to allow the elaboration of the F ring and complete the synthesis.

EPFL2020

Guidelines for performing lignin-first biorefining

Jeremy Luterbacher, Feng Wang

The valorisation of the plant biopolymer lignin is now recognised as essential to enabling the economic viability of the lignocellulosic biorefining industry. In this context, the "lignin-first" biorefining approach, in which lignin valorisation is considered in the design phase, has demonstrated the fullest utilisation of lignocellulose. We define lignin-first methods as active stabilisation approaches that solubilise lignin from native lignocellulosic biomass while avoiding condensation reactions that lead to more recalcitrant lignin polymers. This active stabilisation can be accomplished by solvolysis and catalytic conversion of reactive intermediates to stable products or by protection-group chemistry of lignin oligomers or reactive monomers. Across the growing body of literature in this field, there are disparate approaches to report and analyse the results from lignin-first approaches, thus making quantitative comparisons between studies challenging. To that end, we present herein a set of guidelines for analysing critical data from lignin-first approaches, including feedstock analysis and process parameters, with the ambition of uniting the lignin-first research community around a common set of reportable metrics. These guidelines comprise standards and best practices or minimum requirements for feedstock analysis, stressing reporting of the fractionation efficiency, product yields, solvent mass balances, catalyst efficiency, and the requirements for additional reagents such as reducing, oxidising, or capping agents. Our goal is to establish best practices for the research community at large primarily to enable direct comparisons between studies from different laboratories. The use of these guidelines will be helpful for the newcomers to this field and pivotal for further progress in this exciting research area.

ROYAL SOC CHEMISTRY2021