Tetrahedron
Volume 65, Issue 42,
17 October 2009
, Pages 8603-8655
Author links open overlay panel
Graphical abstract
Introduction
From its humble origins as a mere ‘chemical curiosity,’ radical chemistry has developed into one of the most powerful tools for preparative organic synthesis. Initially considered too reactive to be of use in synthesis, to quote Chatgilialoglu, ‘…most chemists have avoided radical reactions as messy, unpredictable, unpromising, and essentially mysterious,’1 radicals now play a dominant role in the development of novel methodology and have found widespread use in the synthesis of complex natural products. In fact, far from being too reactive to give clean reactions, it is clear that radicals are frequently more selective and predictable than ionic reactions. Radical processes show numerous advantages over their ionic counterparts, including greater functional-group tolerance, the frequent use of pH-neutral conditions and a capability to be incorporated into elaborate reaction cascades that rapidly increase molecular complexity. Furthermore, radical chemistry is amenable to ‘green’ chemistry; there are many examples of radical reactions being performed in water and with a variety of cheap, environmentally benign reagents. Research into radical chemistry continues to blossom and, with the move away from tin-based methodologies, its future is well assured.
The aim of the following two articles is to highlight recent developments in the use of radical reagents and reactions in organic synthesis; as such, it is not intended to be an all-inclusive review. The review is loosely based on the material covered by the author's contributions to Annual Reports on the Progress of Chemistry: Section B,2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f) covering the literature from 2002 to 2007; key publications from 2008 have been included, but the year was not meticulously surveyed. The review concentrates on radical reactions that aid the synthetic chemist and can be performed in any standard organic research laboratory; discussion of both electro- and photochemistry, with the exception of simple UV-light initiation, is limited. Photochemical reactions that do not proceed by a chain process, i.e., the combination of biradicals, have not been included. Similarly, due to the intended practical bias, there is little discussion of fundamental research on the physical properties of radicals and their reactions, such as kinetic experiments. Regrettably, these restrictions mean that many elegant publications are not included; hopefully, the review will stimulate the reader to seek these papers out.
There have been a number of specialist reviews providing comprehensive coverage of various aspects of radical chemistry published over the last five years; topics covered include free-radical cascade processes,3 the synthesis of heterocycles by radical cyclisations,4 the synthesis of five- and six-membered heterocycles,5, 5(a), 5(b) 5-endo-trig cyclisations,6 the formation of five-membered rings by translocation–cyclisation,7 unusual radical cyclisations,8 radical reactions in aqueous media,9 the chemistry of ketyl radical anions formed by photoinduced electron transfer,10 the addition of radicals to C
N bonds,11, 12 ‘clean’ radical reagents,13 phosphorus-based radical methodology,14 indium and indium reagents in organic synthesis,15, 15(a), 15(b) dichloroindane as a versatile reducing agent,16 titanocene-mediated radical reactions,17, 17(a), 17(b) copper(I)-catalysed atom transfer radical cyclisations,18 atom transfer radical polymerisations (ATRP),19, 19(a), 19(b) samarium(II) iodide in organic synthesis,20, 21, 22, 22(a), 22(b), 22(c) samarium(II) iodide in asymmetric synthesis,23 transition metal generated radicals,24 cerium regents in synthesis,25 the persistent radical effect,26, 26(a), 26(b) cyclohexa-1,4-diene-based radical reagents,27 radical additions to aromatic systems,28 diastereoselective radical reactions,29, 29(a), 29(b) enantioselective radical reactions,30, 31, 32 stereoselective conjugate additions.33, 34 radical carbonylations,35 O-centred radicals in C–O bond formation,36 inorganic radical reagents,37 radical chemistry of organoboranes,38, 38(a), 38(b) the addition of phosphorus compounds to unactivated hydrocarbons,39 nitrogen-directed radical rearrangements,40 thiol-mediated radical cyclisations,41 the chemistry of N-centred radicals,42 chirality control in photochemical reactions43 and the carbometallation of unactivated alkenes by zinc enolate derivatives.44 An issue of Tetrahedron: Asymmetry was dedicated to stereoselective radical reactions.45 The nature of the current review means there will be overlap with some of these publications; in all cases, the interested reader is directed towards the specialist review for a more detailed insight.
It is impossible to organise such a substantial body of work to please every reader, or even the author; the original draft of this review was over 350 pages and considerable editing has led to its current structure. To emphasise the synthetic uses of radicals, the review has been divided into two sections; reagents and transformations. Due to the size of the topic, there is an uneven division of material over two issues of Tetrahedron, with reagents and intermolecular additions following this introduction whilst radical cyclisations and rearrangements are found in a forthcoming issue. The first section is not a comprehensive list of every radical initiator and hydride source available, but concentrates on new technologies that aid clean radical reactions. Examples of the utility of each reagent will be given in this section, but the majority of the chemistry will be contained in the subsequent sections. The ability of radicals to partake in cascade reactions and multi-component couplings results in potential overlap between the various sections; for example, a cyclisation could also involve a conjugate addition. Regrettably, this is unavoidable and the author has organised such reactions by the ‘key’ step. A lenient definition of the term ‘radical reaction’ has been employed and, thus, a number of transformations for which the mechanism has either not been determined or may not be ‘free radical’ have been included when deemed appropriate. It is hoped that the review offers a timely overview of the current state of free-radical chemistry in organic synthesis and encourages other researchers to utilise radical chemistry in their own work and, more auspiciously, to further develop this vibrant field.
Section snippets
‘Clean’ tin reagents and procedures
Organotin reagents have been central to the development of free-radical chemistry and their use still underpins many endeavours in this field. Unfortunately, these reagents are plagued by shortcomings; they are toxic, a problem compounded by the recurring difficulty in their complete removal. These deficiencies have severely limited the use of radical chemistry in industrial settings. Considerable effort has been expended attempting to alleviate these failings, or to eliminate the use of tin
Radical reactions
There have been a vast number of publications on radical reactions in the last six years; the author cannot discuss the majority of them and will just highlight the most pertinent. Even so, there is still a large array of reactions and it is hard to organise these in a manner that will please all. The review is very simplistically divided into the following sections; intermolecular additions are found in this issue and then a subsequent issue of Tetrahedron will include cyclisations and
Conclusions
No longer a mere curiosity, the chemistry of radicals now attracts considerable attention, due to its versatility and attractive properties. With the shift in emphasis away from tin-based protocols, the last obstacle to the widespread acceptance of radical chemistry is being removed. The ‘green’ credentials of radical transformations means that they will undoubtedly play an important role in synthetic chemistry in the coming years. As Section 2 reveals, many alternatives to tin-based reagents
Acknowledgements
I would like to thank all my colleagues who have helped shape both this review and the Annual Reports on which it was based; in no particular order these include Prof. Phil Page, Prof. William Motherwell, Associate Prof. Trevor Kitson and Dr. Martyn Coles. Iam also grateful to all the authors who were kind enough to respond to my many requests for reprints and information. Finally, a thank you to Prof. Jim Hanson, whose efforts are never acknowledged enough.
Gareth J. Rowlands was born and raised in Horsham, West Sussex, UK. He obtained his first degree from Imperial College, London and stayed there to complete his PhD under the supervision of Donald Craig. In 1996 he joined Prof. Steven V. Ley's group at Cambridge University as a Royal Commission for the Exhibition of 1851 Research Fellow. After three years, he moved to Brighton to take up a lectureship in organic chemistry at the University of Sussex. Seven years and a few grey hairs later, he
First page preview
Click to open first page preview
References and notes (325)
- H. Miyabe et al.
Org. Lett.
(2002)
H. Miyabe et al.Tetrahedron
(2004)
- R. Yanada et al.
J. Org. Chem.
(2004)
- M. Benedetti et al.
Tetrahedron
(1997)
A.J. Clark et al.J. Chem. Soc., Perkin Trans. 1
(2000)
A.J. Clark et al.(Video) Radicals in organic synthesisTetrahedron Lett.
(1999)
R.P. Filik et al.J. Org. Chem.
(1999)
F. de Campo et al.Chem. Commun.
(1998)
F. de Campo et al.J. Chem. Soc., Perkin Trans. 1
(2000)
F. Ghelfi et al.Tetrahedron
(1999)
- H. Nagashima et al.
J. Org. Chem.
(1993)
- S.K. Mandal et al.
Tetrahedron Lett.
(2005)
- A.F. Barrero et al.
J. Org. Chem.
(2002)
- A. Gansäuer et al.
J. Am. Chem. Soc.
(1998)
- K. Inoue et al.
J. Am. Chem. Soc.
(2002)
B.C. Ranu et al.Tetrahedron Lett.
(2004)
- T. Miyai et al.
Tetrahedron Lett.
(1998)
- D.H.R. Barton et al.
J. Org. Chem.
(1993)
Organosilanes in Radical Chemistry
(2004)
Synlett
(2004)
J. Am. Chem. Soc.
(1997)
P. Pike et al.Tetrahedron
(1988)
A.L.J. Beckwith et al.J. Am. Chem. Soc.
(1986)
P. Pike et al.Tetrahedron Lett.
(1985)
J. Chem. Soc., Perkin Trans. 1
(2000)
Chem. Soc. Rev.
(2001)
Chem.—Eur. J.
(2007)
Chem. Rev.
(2004)
Chem. Soc. Rev.
(2002)
Adv. Synth. Catal.
(2002)
A.F. Barrero et al.Eur. J. Org. Chem.
(2006)
Chem. Rec.
(2005)
Tetrahedron
(2001)
Tetrahedron
(2006)
Acc. Chem. Res.
(1992)
Annu. Rep. Prog. Chem., Sect. B
(2003)
G.J. RowlandsAnnu. Rep. Prog. Chem., Sect. B
(2004)
G.J. RowlandsAnnu. Rep. Prog. Chem., Sect. B
(2005)
G.J. RowlandsAnnu. Rep. Prog. Chem., Sect. B
(2006)
G.J. RowlandsAnnu. Rep. Prog. Chem., Sect. B
(2007)
G.J. RowlandsAnnu. Rep. Prog. Chem., Sect. B
(2008)
Angew. Chem., Int. Ed.
(2001)
J. Chem. Soc., Perkin Trans. 1
(2002)
Tetrahedron
(2007)
K.C. Majumdar et al.Tetrahedron
(2005)
Synthesis
(2002)
Synlett
(2008)
Radicals in Synthesis II: Complex Molecules
(2006)
Synlett
(2002)
Tetrahedron
(2007)
Synthesis
(2002)
Chem. Soc. Rev.
(2005)
Tetrahedron
(2004)
J. Podlech et al.Synthesis
(2003)
Curr. Org. Chem.
(2002)
T. Pintauer et al.Chem. Soc. Rev.
(2008)
Org. Biomol. Chem.
(2006)
Synlett
(2005)
H.B. KaganTetrahedron
(2003)
M. Berndt et al.Synlett
(2004)
New J. Chem.
(2008)
J. Organomet. Chem.
(2002)
Acc. Chem. Res.
(2004)
Chem. Soc. Rev.
(2004)
A. Studer et al.Chem. Rec.
(2005)
Acc. Chem. Res.
(2005)
Chem. Soc. Rev.
(2007)
Chem. Soc. Rev.
(2003)
Chem. Rev.
(2003)
Top. Curr. Chem.
(2006)
Tetrahedron
(2005)
Angew. Chem., Int. Ed.
(2006)
Synthesis
(2002)
Cited by (172)
Electron / hole catalysis: A versatile strategy for promoting chemical transformations
2022, Tetrahedron
Electron transfer is a fundamental chemical process that adds an electron into one chemical entity and generates a hole in another. Both the additional electron and the corresponding hole exhibit remarkable catalytic effects in promoting chemical transformations. In this Perspective, by classifying the implementation methods of electron/hole catalysis into four categories—namely, chemical, electrochemical, photochemical and mechanochemical means—we summarize the recent progress in this burgeoning field of research, focusing on the elegant ways that have been developed to inject or remove electrons into or from reaction systems under mild conditions. Moreover, recent advances in research involving the applications of electron/hole catalysis in molecular switches and supramolecular assemblies are also highlighted in order to show the versatility and potential of this strategy in all aspects of contemporary chemistry including, but not limited to, organic synthesis.
Atom-transfer radical cyclization of α-bromocarboxamides under organophotocatalytic conditions
2021, Tetrahedron Letters
The atom-transfer radical cyclization (ATRC) reaction gives halogenated heterocycles from the corresponding halocarbonyls that possess a C–C double bond. In contrast, the reductive ATRC reaction gives non-halogenated heterocycles in the presence of a reductant. In this research, we successfully control the ATRC and reductive ATRC reactions of N-allyl-α-haloamides under visible-light irradiation in the presence/absence of the Hantzsch ester as a reductant.
Generation of powerful organic electron donors by water-assisted decarboxylation of benzimidazolium carboxylates
2021, Organic Chemistry Frontiers
Organic electron donors (OEDs) are increasingly used as efficient reducing agents in various radical reactions. However, their sensitivity to air restraints their practical use and the development of further industrial applications. To meet the community's needs, this paper reports the preparation of air- and moisture-stable carboxylate precursors that can be conveniently activated into the corresponding organic reducer. The new strategy consists in the water-assisted decarboxylation of the adduct at room temperature, providing a straightforward protocol for the single-electron transfer reduction of aryl halides and sulfonamide. The resulting aryl radicals are engaged in the first examples of OED-promoted intermolecular addition reactions. A thorough mechanistic study supports the in situ formation of the organic reducer.
Radical Reactions in Alkaloid Synthesis: A Perspective from Carbon Radical Precursors
2020, European Journal of Organic Chemistry
The usefulness of radical reactions in alkaloid synthesis is reviewed from the perspective of the functional groups embedded in the molecular structure of synthetic intermediates, that act as precursors of carbon‐centered radicals in the construction of new C–C bonds. The functional groups featured are alkenes, alkynes, halides (alkyl, vinyl, aryl), xanthates, sulfides, selenides, aldehydes, ketones, carboxylic acid derivatives (selenoesters, haloacetamides), β‐dicarbonyl compounds, and α‐heterosubstituted nitrogen‐compounds. The use of nitrogen‐centered radicals for C–N bond formation is also covered. Among the variety of radical processes applied, the most predominant are the hydride reductive method (Sn, Si), atom transfer radical reactions (Cu, Ru, B), and single‐electron transfer radical reactions promoted by Sm, Ni, Fe, Mn, Ti, and Ag. This review showcases the role radical reactions have played in the recent development of new strategies in alkaloid synthesis, as well as the implementation of new radical procedures in demanding substrates.
Photocatalysis: A step closer to the perfect synthesis
2020, Journal of Organometallic Chemistry
The complexity of molecules with biological and therapeutic interests is still growing and still creating continuous challenges that are faced with the development of the synthesis strategies taking into account the environmental issues. Photocatalysis has became a pillar of engineering molecular structures that accelerated the development and afforded complementarity to diverse reaction processes; this method consists of the use of light sources in order to excite catalysts that are able to activate a variety of substrates in a controlled and predictable manner. Photocatalysis could be considered as one of the cleanest synthesis pathways due to the mild condition used where neither high temperatures nor notorious materials are used. This outlook aims to highlight recent developments of photocatalyzed strategies that permit to undergo functionalization, cycloaddition, and coupling reactions.
(Video) A Level Chemistry "Free Radical Substitution of Alkanes"Highly Cumulated Radical Cascade Reaction of aza-1,6-Enyenes: Stereoselective Synthesis of exo-Methylene Piperidines
2020, European Journal of Organic Chemistry
Treatment of 1,6‐azaeneyne compounds with Ph3SnH resulted in the stereoselective formation of 5‐(E)‐alkylidene‐2,3‐cis‐piperidine in moderate to good yields. Intermediate products including methylenepyrrolidine and stannomethylene pyrrolidine were also detected in the reaction mixture, suggesting that the reaction progressed via a highly cumulated radical cascade process involving sequential six radical processes, i.e. radical addition, 5‐exo cyclization, substitution (1,4‐tin migration), 3‐exo cyclization, ring cleavage of cycloprolane, and hydrogen abstraction from Ph3SnH. The product distribution depended on the lower Ph3SnH concentration, resulting in higher piperidine yields. The E/Z selectivity of the exo‐methylene unit was also sensitive to the reaction temperature. The vinylic triphenyltin group was converted into hydrogen and iodine. A kinetic analysis of the reaction indicated that the 1,4‐tin migration and ring expansion progressed as irreversible reactions and that their reaction rates were large enough to progress the cascade reaction smoothly and to prevent side reactions such as hydrogen abstraction from Ph3SnH.
Recommended articles (6)
Research article
Desymmetrization of meso-methylenecyclopropanes by a palladium-catalyzed asymmetric ring-opening bis(alkoxycarbonylation) reaction
Tetrahedron: Asymmetry, Volume 25, Issue 12, 2014, pp. 936-943
Desymmetrization of various meso-methylenecyclopropanes was accomplished by a palladium-catalyzed asymmetric ring-opening bis(alkoxycarbonylation) reaction employing a chiral bioxazoline ligand. The reaction proceeded smoothly in the presence of copper(I) triflate under carbon monoxide and oxygen at ambient pressure to give the corresponding optically active α-methyleneglutarates with up to 60% ee. Desymmetrization of protected meso-(3-methylenecyclopropane-1,2-diyl)dimethanols was also carried out to give enantioenriched highly oxygen-functionalized α-methyleneglutarates.
Research article
Concise and direct construction of cis-pyrano[4,3-b]pyran-5-one skeleton from glucal derivatives: synthesis of ent-4-deoxy-2,3-di-epi-dinemasone BC
Tetrahedron Letters, Volume 56, Issue 37, 2015, pp. 5228-5230
(−)-Dinemasones B and C were isolated from a culture of the endophytic fungus Dinemasporium strigosum and had shown attractive antimicrobial activities in vitro. Described herein is the concise synthesis of their analogue, ent-4-deoxy-2,3-di-epi-dinemasone BC, from glucal derivatives, including C-glycoside and 3-deoxy-glucal, and the strategies proceeded in 7 steps in 13% overall yield and in 9 steps in 17% overall yield respectively.
Research article
Vanadium(V)-mediated rearrangement/halogenation cascade: Synthesis of α-haloenones from propargyl alcohols
Tetrahedron, Volume 73, Issue 29, 2017, pp. 4115-4124
A method is described for the oxidative Meyer–Schuster-type rearrangement of propargylic alcohols to (Z)-α-chloro- and α-iodoenones using VOCl3 as a multifunctional reagent. The vanadium reagent is found to serve as rearrangement promoter as well as an active chlorenium ion donor. Yields are improved when VOCl3 is employed in conjunction with N-halosuccinimide reagents, giving some insights into the complex mechanism.
Research article
Mn(III)-based reaction of alkenes with quinolinones. Formation of peroxyquinolinones and quinoline-related derivatives
Tetrahedron, Volume 70, Issue 7, 2014, pp. 1437-1450
The reactions of 1,1-disubstituted alkenes with 4-hydroxyquinolin-2(1H)-ones under both Mn(III)-catalyzed aerobic oxidation conditions at room temperature and Mn(III)-mediated oxidation conditions at reflux temperature are described. The Mn(III)-catalyzed aerobic oxidation afforded bis(hydroperoxyethyl)quinolinones and azatrioxa[4.4.3]propellanes, while the oxidation with Mn(OAc)3·2H2O produced furo[3,2-c]quinolin-4-one analogues. The existence of a substituent at the 3-position of the 4-hydroxyquinolin-2(1H)-ones prevented a double reaction with the alkenes, and (endoperoxy)quinolinones and/or (hydroperoxyethyl)quinolinones were obtained under the Mn(III)-catalyzed aerobic conditions, while furo[3,2-c]quinolinone hemiacetals and vinylquinolinones were selectively produced under the Mn(III)-mediated oxidation conditions depending on the reaction temperature and times. Cyclic assembly of quinolinone-related 1,3-dicarbonyl compounds such as dihydropyridinones, pyranones, and dimedone derivatives was also examined under elevated temperature conditions.
Research article
Ortho-lithiation reaction of aryl triflones
Tetrahedron, Volume 74, Issue 39, 2018, pp. 5635-5641
The ortho-lithiation of substituted arenes is a powerful methodology to synthesize ortho-substituted arenes. While a wide variety of directed metalation groups (DMGs) have been reported, trifluoromethyl sulfone has never been used. We disclose the first example of ortho-lithiation of aryl triflones. We found that the trifluoromethyl sulfonyl group is not only an important structural motif in biologically active molecules and specialty materials, but also an excellent DMG moiety for ortho-metalation reactions. The use of a base that causes steric hindrance, LTMP, is the key for successful transformation to furnish a variety of ortho-substituted aryl triflones in good yields. Further functionalization of resulting ortho-substituted aryl triflones was demonstrated by metal-catalyzed coupling reactions.
Research article
Carbon–carbon bond formation via benzoyl umpolung attained by photoinduced electron-transfer with benzimidazolines
Tetrahedron Letters, Volume 54, Issue 50, 2013, pp. 6874-6877
A photoreaction between benzoyl compounds, such as benzoylformate derivatives, and 2-(p-anisyl)-1,3-dimethylbenzimidazoline in the presence of allyl bromide was found to give various allylated alcohols. In the reaction of benzoylformates, α-hydroxy ester enolates, for which the negative charge occurs on the carbonyl carbon of benzoyl (umpolung reactivity), are proposed to be generated as intermediates by electron-transfer from benzimidazolines to the photoexcited benzoylformates; these species react with allyl bromide to produce α-allyl-α-hydroxy esters.
Gareth J. Rowlands was born and raised in Horsham, West Sussex, UK. He obtained his first degree from Imperial College, London and stayed there to complete his PhD under the supervision of Donald Craig. In 1996 he joined Prof. Steven V. Ley's group at Cambridge University as a Royal Commission for the Exhibition of 1851 Research Fellow. After three years, he moved to Brighton to take up a lectureship in organic chemistry at the University of Sussex. Seven years and a few grey hairs later, he moved to New Zealand where he is currently enjoying life as a senior lecturer at Massey University. He loves chemistry a little too much to be healthy and, when forced to narrow his interests, he professes to be intrigued by enantioselective catalysis, organocatalysis, radicals and, of course, the chemistry of [2.2]paracyclophane. Dr. Rowlands has been interested in science since his first encounter with Dr. Egon Spengler, and whilst chemistry may not be so esoteric, it is often equally enigmatic.
Copyright © 2009 Elsevier Ltd. All rights reserved.
FAQs
What are radicals in organic chemistry? ›
In chemistry, a radical (more precisely, a free radical) is an atom, molecule, or ion that has unpaired valence electrons or an open electron shell, and therefore may be seen as having one or more "dangling" covalent bonds.
How do radicals work organic chemistry? ›In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spontaneously dimerize. Most organic radicals have short lifetimes.
How do you rank radicals in order of stability? ›Stability increases in the order methyl (least stable) < primary < secondary < tertiary (most stable) Free radicals are stabilized by resonance. Free radicals are stabilized by adjacent atoms with lone pairs. Free radicals increase in stability as the electronegativity of the atom decreases.
What are radicals and electron-deficient species? ›A free radical is a species containing one or more unpaired electrons. Free rad- icals are electron-deficient species, but they are usually uncharged, so their chem- istry is very different from the chemistry of even-electron electron-deficient species such as carbocations and carbenes.