Query: Organic synthesis

Candidate papers:

abstract: A fundamental aim in the field of catalysis is the development of new modes of small molecule activation. One approach toward the catalytic activation of organic molecules that has received much attention recently is visible light photoredox catalysis. In a general sense, this approach relies on the ability of metal complexes and organic dyes to engage in single electron transfer (SET) processes with organic substrates upon photoexcitation with visible light. Many of the most commonly employed visible light photocatalysts are polypyridyl complexes of ruthenium and iridium, and are typified by the complex tris(2,2' bipyridine) ruthenium(II) or Ru(bpy)32+ (Figure 1) These complexes absorb light in the visible region of the electromagnetic spectrum to give stable, long lived photoexcited states.1,2 The lifetime of the excited species is sufficiently long (1100 ns for Ru(bpy)32+ that it may engage in bimolecular electron transfer reactions in competition with deactivation pathways.3 Although these species are poor single electron oxidants and reductants in the ground state, excitation of an electron affords excited states that are very potent single electron transfer reagents. Importantly, the conversion of these bench stable, benign catalysts to redox active species upon irradiation with simple household lightbulbs represents a remarkably chemoselective trigger to induce unique and valuable catalytic processes. Figure 1 Ruthenium polypyridyl complexes: versatile visible light photocatalysts. The ability of Ru(bpy)32+ and related complexes to function as visible light photocatalysts has been recognized and extensively investigated for applications in inorganic and materials chemistry. In particular, photoredox catalysts have been utilized to accomplish the splitting of water into hydrogen and oxygen4 and the reduction of carbon dioxide to methane.5 Ru(bpy)32+ and its analogues have been used (i) as components of dye sensitized solar cells6 and organic light emitting diodes,7 (ii) to initiate polymerization reactions,8 and (iii) in photo dynamic therapy.9 Until recently, however, these complexes had been only sporadically employed as photocatalysts in the area of organic synthesis. The limited exploration of this area is perhaps surprising, as single electron, radical processes have long been employed in C C bond construction and often provide access to reactivity that is complementary to that of closed shell, two electron pathways.10 In 2008, concurrent reports from the Yoon group and our own lab detailed the use of Ru(bpy)32+ as a visible light photoredox catalyst to perform a [2 2] cycloaddition11 and an a alkylation of aldehydes,12 respectively. Shortly thereafter, Stephenson and co workers disclosed a photoredox reductive dehalogenation of activated alkyl halides mediated by the same catalyst.13 The combined efforts of these three research groups have helped to initiate a renewed interest in this field, prompting a diversity of studies into the utility of photoredox catalysis as a conceptually novel approach to synthetic organic reaction development. Much of the promise of visible light photoredox catalysis hinges on its ability to achieve unique, if not exotic bond constructions that are not possible using established protocols. For instance, photoredox catalysis may be employed to perform overall redox neutral reactions. As both oxidants and reductants may be transiently generated in the same reaction vessel, photoredox approaches may be used to develop reactions requiring both the donation and the reception of electrons at disparate points in the reaction mechanism. This approach stands in contrast to methods requiring stoichiometric chemical oxidants and reductants, which are often incompatible with each other, as well as to electrochemical approaches, which are not amenable to redox neutral transformations. Furthermore, single electron transfer events often provide access to radical ion intermediates having reactivity patterns fundamentally different from those of their ground electronic or excited states.14 Access to these intermediates using other means of activation is often challenging or requires conditions under which their unique reactivity cannot be productively harnessed. At the same time, photoredox catalysts such as Ru(bpy)32+ may also be employed to generate radicals for use in a diverse range of established radical chemistries. Photoredox reactions occur under extremely mild conditions, with most reactions proceeding at room temperature without the need for highly reactive radical initiators. The irradiation source is typically a commercial household light bulb, a significant advantage over the specialized equipment required for processes employing high energy ultraviolet (UV) light. Additionally, because organic molecules generally do not absorb visible light, there is little potential for deleterious side reactions that might arise from photoexcitation of the substrate itself. Finally, photoredox catalysts may be employed at very low loadings, with 1 mole or less being typical. This Review will highlight the early work on the use of transition metal complexes as photoredox catalysts to promote reactions of organic compounds (prior to 2008) as well as cover the surge of work that has appeared since 2008. We have for the most part grouped reactions according to whether the organic substrate undergoes reduction, oxidation, or a redox neutral reaction and throughout have sought to highlight the variety of reactive intermediates that may be accessed via this general reaction manifold.15 Studies on the use of transition metal complexes as visible light photocatalysts for organic synthesis have benefited tremendously from advances in the related fields of organic and semiconductor photocatalysis. Many organic molecules may function as visible light photocatalysts; analogous to metal complexes such as Ru(bpy)32+ organic dyes such as eosin Y, 9,10 dicyanoanthracene, and triphenylpyrylium salts absorb light in the visible region to give excited states capable of single electron transfer. These catalysts have been employed to achieve a vast range of bond forming reactions of broad utility in organic synthesis.16 Visible light photocatalysis has also been carried out with heterogeneous semiconductors such as mesoporous carbon nitride17 and various metal oxides and sulfides.18 These approaches are often complementary to photoredox catalysis with transition metal polypyridyl complexes, and we have referred to work in these areas when it is similar to the chemistry under discussion. However, an in depth discussion of the extensive literature in these fields is outside the scope of this Review, and readers are directed to existing reviews on these topics.16 18
author_names: Christopher K Prier

Danica A Rankic

David W C MacMillan
title: Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis.
venue: Chemical reviews
year: 2013

abstract: This Review is aimed at synthetic organic chemists who may be familiar with organometallic catalysis but have no experience with biocatalysis, and seeks to provide an answer to the perennial question: if it is so attractive, why wasn't it extensively used in the past? The development of biocatalysis in industrial organic synthesis is traced from the middle of the last century. Advances in molecular biology in the last two decades, in particular genome sequencing, gene synthesis and directed evolution of proteins, have enabled remarkable improvements in scope and substantially reduced biocatalyst development times and cost contributions. Additionally, improvements in biocatalyst recovery and reuse have been facilitated by developments in enzyme immobilization technologies. Biocatalysis has become eminently competitive with chemocatalysis and the biocatalytic production of important pharmaceutical intermediates, such as enantiopure alcohols and amines, has become mainstream organic synthesis. The synthetic space of biocatalysis has significantly expanded and is currently being extended even further to include new to nature biocatalytic reactions.
author_names: Roger Arthur Sheldon

Dean Brady
title: Broadening the Scope of Biocatalysis in Sustainable Organic Synthesis.
venue: ChemSusChem
year: 2019

abstract: Nature is capable of storing solar energy in chemical bonds via photosynthesis through a series of C C, C O and C N bond forming reactions starting from CO2 and light. Direct capture of solar energy for organic synthesis is a promising approach. Lead (Pb) halide perovskite solar cells reach 24.2% power conversion efficiency, rendering perovskite a unique type material for solar energy capture. We argue that photophysical properties of perovskites already proved for photovoltaics, also should be of interest in photoredox organic synthesis. Because the key aspects of these two applications are both relying on charge separation and transfer. Here we demonstrated that perovskites nanocrystals are exceptional candidates as photocatalysts for fundamental organic reactions, for example C C, C N and C O bond formations. Stability of CsPbBr3 in organic solvents and ease of tuning their bandedges garner perovskite a wider scope of organic substrate activations. Our low cost, easy to process, highly efficient, air tolerant and bandedge tunable perovskites may bring new breakthrough in organic chemistry.While photoredox catalysis provides organic chemistry new avenues for chemical reactions, typical photocatalysts require expensive noble metals and show modest stabilities. Here, authors examine lead halide perovskites nanocrystals as stable and tunable photoredox catalysts for organic synthesis.
author_names: Xiaolin Zhu

Yixiong Lin

Jovan San Martin

Yue Sun

Dian Zhu

Yong Yan
title: Lead halide perovskites for photocatalytic organic synthesis
venue: Nature Communications
year: 2019

abstract: Clear directions for a robotic platform The chemistry literature contains more than a century's worth of instructions for making molecules, all written by and for humans. Steiner et al. developed an autonomous compiler and robotic laboratory platform to synthesize organic compounds on the basis of standardized methods descriptions (see the Perspective by Milo) The platform comprises conventional equipment such as round bottom flasks, separatory funnels, and a rotary evaporator to maximize its compatibility with extant literature. The authors showcase the system with short syntheses of three common pharmaceuticals that proceeded comparably to manual synthesis. Science, this issue p. eaav2211; see also p. 122 A compiler directs a robotic platform to conduct short organic syntheses using standard protocols and laboratory equipment. INTRODUCTION Outside of a few well defined areas such as polypeptide and oligonucleotide chemistry, the automation of chemical synthesis has been limited to large scale bespoke industrial processes, with laboratory scale and discovery scale synthesis remaining predominantly a manual process. These areas are generally defined by the ability to synthesize complex molecules by the successive iteration of similar sets of reactions, allowing the synthesis of products by the automation of a relatively small palette of standardized reactions. Recent advances in areas such as flow chemistry, oligosaccharide synthesis, and iterative cross coupling are expanding the number of compounds synthesized by automated methods. However, there is no universal and interoperable standard that allows the automation of chemical synthesis more generally. RATIONALE We developed a standard approach that mirrors how the bench chemist works and how the bulk of the open literature is reported, with the round bottomed flask as the primary reactor. We assembled a relatively small array of equipment to accomplish a wide variety of different syntheses, and our abstraction of chemical synthesis encompasses the four key stages of synthetic protocols: reaction, workup, isolation, and purification. Further, taking note of the incomplete way chemical procedures are reported, we hypothesized that a standardized format for reporting a chemical synthesis procedure, coupled with an abstraction and formalism linking the synthesis to physical operations of an automated robotic platform, would yield a universal approach to a chemical programming language. We call this architecture and abstraction the Chemputer. RESULTS For the Chemputer system to accomplish the automated synthesis of target molecules, we developed a program, the Chempiler, to produce specific, low level instructions for modular hardware of our laboratory scale synthesis robot. The Chempiler takes information about the physical connectivity and composition of the automated platform, in the form of a graph using the open source GraphML format, and combines it with a hardware independent scripting language [chemical assembly (ChASM) language] which provides instructions for the machine operations of the automated platform. The Chempiler software allows the ChASM code for a protocol to be run without editing on any unique hardware platform that has the correct modules for the synthesis. Formalization of a written synthetic scheme by using a chemical descriptive language (XDL) eliminates the ambiguous interpretation of the synthesis procedures. This XDL scheme is then translated into the ChASM file for a particular protocol. An automated robotic platform was developed, consisting of a fluidic backbone connected to a series of modules capable of performing the operations necessary to complete a synthetic sequence. The backbone allows the efficient transfer of the required chemicals into and out of any module of the platform, as well as the flushing and washing of the entire system during multistep procedures in which the modules are reused multiple times. The modules developed for the system consist of a reaction flask, a jacketed filtration setup capable of being heated or cooled, an automated liquid liquid separation module, and a solvent evaporation module. With these four modules, it was possible to automate the synthesis of the pharmaceutical compounds diphenhydramine hydrochloride, rufinamide, and sildenafil without human interaction, in yields comparable to those achieved in traditional manual syntheses. CONCLUSION The Chemputer allows for an abstraction of chemical synthesis, when coupled with a high level chemical programming language, to be compiled by our Chempiler into a low level code that can run on a modular standard robotic platform for organic synthesis. The software and modular hardware standards permit synthetic protocols to be captured as digital code. This code can be published, versioned, and transferred flexibly between physical platforms with no modification. We validated this concept by the automated synthesis of three pharmaceutical compounds. This represents a step toward the automation of bench scale chemistry more generally and establishes a standard aiming at increasing reproducibility, safety, and collaboration. Abstraction of organic synthesis to the Chemputer software and hardware standards. The Chemputer system can perform multistep organic synthesis protocols on the bench by using a modular system with hardware and software standards. The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform by using a chemical programming language that formalizes and controls the assembly of the molecules. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, diphenhydramine hydrochloride, rufinamide, and sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex molecules.
author_names: Sebastian Steiner

Jakob Wolf

Stefan Glatzel

Anna Andreou

Jaroslaw M Granda

Graham Keenan

Trevor Hinkley

Gerardo Aragon-Camarasa

Philip J Kitson

Davide Angelone

Leroy Cronin
title: Organic synthesis in a modular robotic system driven by a chemical programming language
venue: Science
year: 2019

abstract: AbstractDespite decades of ground breaking research in academia, organic synthesis is still a rate limiting factor in drug discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non traditional disconnections, more C H bond activation and late stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C X or C C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.Organic synthesis is a rate limiting factor in drug discovery, so the pharmaceutical industry heavily relies on academic research. This Perspective highlights some of the most pressing challenges to be overcome from the industrial viewpoint such as the development of reactions tolerating specific functionalities and encourages stronger industry academia relationships. Credit: Pills image: Profimedia.CZ a.s. Alamy Stock Photo; Factory image: Diana Johanna Velasquez Alamy Stock Vector; Graduate hat: Michael Burrell Alamy Stock Photo; Conical flask: Astex.
author_names: David C Blakemore

Luis Castro

Ian Churcher

David Charles Rees

Andrew William Thomas

David M Wilson

Anthony Wood
title: Organic synthesis provides opportunities to transform drug discovery
venue: Nature Chemistry
year: 2018

abstract: Visible light photocatalysis has evolved over the last decade into a widely used method in organic synthesis. Photocatalytic variants have been reported for many important transformations, such as cross coupling reactions, a amino functionalizations, cycloadditions, ATRA reactions, or fluorinations. To help chemists select photocatalytic methods for their synthesis, we compare in this Review classical and photocatalytic procedures for selected classes of reactions and highlight their advantages and limitations. In many cases, the photocatalytic reactions proceed under milder reaction conditions, typically at room temperature, and stoichiometric reagents are replaced by simple oxidants or reductants, such as air, oxygen, or amines. Does visible light photocatalysis make a difference in organic synthesis? The prospect of shuttling electrons back and forth to substrates and intermediates or to selectively transfer energy through a visible light absorbing photocatalyst holds the promise to improve current procedures in radical chemistry and to open up new avenues by accessing reactive species hitherto unknown, especially by merging photocatalysis with organo or metal catalysis.
author_names: Leyre Marzo

Santosh K Pagire

Oliver Reiser

Burkhard Konig
title: Visible Light Photocatalysis: Does It Make a Difference in Organic Synthesis?
venue: Angewandte Chemie
year: 2018

abstract: Abstract The direct synthetic organic use of electricity is currently experiencing a renaissance. More synthetically oriented laboratories working in this area are exploiting both novel and more traditional concepts, paving the way to broader applications of this niche technology. As only electrons serve as reagents, the generation of reagent waste is efficiently avoided. Moreover, stoichiometric reagents can be regenerated and allow a transformation to be conducted in an electrocatalytic fashion. However, the application of electroorganic transformations is more than minimizing the waste footprint, it rather gives rise to inherently safe processes, reduces the number of steps of many syntheses, allows for milder reaction conditions, provides alternative means to access desired structural entities, and creates intellectual property (IP) space. When the electricity originates from renewable resources, this surplus might be directly employed as a terminal oxidizing or reducing agent, providing an ultra sustainable and therefore highly attractive technique. This Review surveys recent developments in electrochemical synthesis that will influence the future of this area.
author_names: Anton Wiebe

Tile Gieshoff

Sabine Moehle

Eduardo Rodrigo

Michael Zirbes

Siegfried R Waldvogel
title: Electrifying Organic Synthesis
venue: Angewandte Chemie
year: 2018

abstract: Continuous flow photochemistry in microreactors receives a lot of attention from researchers in academia and industry as this technology provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up to date overview is given of photochemical transformations in continuous flow reactors, including applications in organic synthesis, material science, and water treatment. In addition, the advantages of continuous flow photochemistry are pointed out and a thorough comparison with batch processing is presented.
author_names: Dario Cambie

Cecilia Bottecchia

Natan J W Straathof

Volker Hessel

Timothy Noel
title: Applications of Continuous Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment.
venue: Chemical reviews
year: 2016

abstract: Photocatalysis, the use of light to promote organic transformations, is a field of catalysis that has received limited attention despite existing for over 100 years. With the revolution of photoredox catalysis in 2008, the rebirth or awakening of the field of photoorganocatalysis has brought new ideas and reactions to organic synthesis. This review will focus on the sudden outburst of literature regarding the use of small organic molecules as photocatalysts after 2013. In particular, it will focus on acridinium salts, benzophenones, pyrylium salts, thioxanthone derivatives, phenylglyoxylic acid, BODIPYs, flavin derivatives, and classes of organic molecules as catalysts for the photocatalytic generation of C C and C X bonds.
author_names: Ioanna K Sideri

Errika Voutyritsa

Christoforos G Kokotos
title: Photoorganocatalysis, small organic molecules and light in the service of organic synthesis: the awakening of a sleeping giant.
venue: Organic biomolecular chemistry
year: 2018

abstract: Ionic liquids (ILs) have now been acknowledged as reaction media for biotransformations. The first three examples were reported in this field in 2000, and since then, numerous applications have been reported for biocatalytic reactions using ILs. Two topics using ILs for enzymatic reactions have been reviewed from the standpoint of biocatalyst mediating organic synthesis; the first is "Biocatalysis in Ionic Liquids" which includes various types of biocatalytic reactions in ILs (section 2) (1) recent examples of lipase mediated reactions using ILs as reaction media for biodiesel oil production and for sugar ester production, (2) oxidase catalyzed reactions in ILs, (3) laccase catalyzed reactions, (4) peroxidase catalyzed reactions, (4) cytochrome mediated reactions, (5) microbe mediated hydrations, (6) protease catalyzed reactions, (8) whole cell mediated asymmetric reduction of ketones, (10) acylase catalyzed reactions, (11) glycosylation or cellulase mediated hydrolysis of polysaccharides, (12) hydroxynitrile lyase catalyzed reaction, (13) fluorinase or haloalkane dehydrogenase catalyzed reaction, (14) luciferase catalyzed reactions, and (15) biocatalytic promiscuity of enzymatic reactions for organic synthesis using ILs. The second is "Enzymes Activated by Ionic Liquids for Organic Synthesis" particularly describing the finding story of activation of lipases by the coating with a PEG substituted IL (section 3) The author's opinion toward "Future Perspectives of Using ILs for Enzymatic Reactions" has also been discussed in section 4.
author_names: Toshiyuki Itoh
title: Ionic Liquids as Tool to Improve Enzymatic Organic Synthesis.
venue: Chemical reviews
year: 2017