radical chemistry has always taken a backseat to 
 ionic chemistry . 
 in the basic undergraduate curriculum of organic synthesis , the aldol 
 reaction , grignard addition , and pericyclic transformations like the 
 diels  alder reaction are at the forefront . more advanced texts highlight the vital modern - day use 
 of cross - coupling . however , little emphasis 
 is placed on topics pertaining to radicals . this radical  discrimination might be due to a historically accepted notion that these species 
 are chaotic , uncontrollable , and mysteriously baffling . despite these misconceptions , a plethora of useful 
 and elegant chemistry has been developed over the years using radical 
 intermediates . to properly put this perspective 
 in context , figure 1 outlines some of the great milestones in radical chemistry . the emergence of the first useful radical processes actually 
 preceded 
 fundamental understanding of these chemical entities , as seen with 
 the kolbe electrochemical decarboxylation , the borodin  hunsdiecker reaction , and the hofmann discovery of the pinacol coupling spawned modern means of harnessing ketyl radicals , such as the mcmurry coupling and the kagan reagent ( first report in 1977 ) , while the mechanistically similar 
 acyloin reaction enabled sheehan to achieve tremendous advances in steroid synthesis . gomberg discovered the existence 
 of the trityl radical as a trivalent species , and kharasch realized that radicals could allow one to access 
 anti - markovnikov selectivity in an early example of atom - transfer 
 reaction . shortly afterward , bachmann postulated the persistent radical 
 effect ( pre ) , suggesting the preferential coupling between persistent 
 and fleeting radical species , thus laying a foundation for the rational 
 design of radical reactions ( vide infra ) . studies by hey and waters unraveled the intricacies of homolytic 
 aromatic substitution which form the tenets of radical arene functionalization . the meerwein arylation showcased the possibility 
 of utilizing high - energy aryl radicals in the hydroarylation 
 of olefins . the birch reduction opened 
 up a new dimension to the synthetic utility of arenes . waters s thiol - catalyzed aldehyde homolysis in 1952 
 provided 
 efficient means of accessing acyl radicals ; it also raised stimulating discussions on radical polar effects , 
 which were extensively examined by walling , leading to the entire area of polarity reversal catalysis . studies into stannanes allowed for the mild 
 and chemoselective generation of carbon - centered radicals , setting 
 the stage for later synthetic applications . oxidative homolysis of alkyl boranes was later found 
 to offer another means of accessing these radicals at low temperatures . around this time , the barton nitrite photolysis 
 was invented , the 
 impact of which in solving a real - world problem ( procurement of aldosterone 
 acetate ) was eye - opening . this reaction , 
 together with breslow s remote radical functionalization , demonstrated 
 the immense power of radical translocation . the seeds of what would later become extremely useful transformations 
 were planted starting in the late 1960s with the discovery of mn(iii)-mediated 
 oxidative additions to olefins , radical - cation - mediated 
 cycloadditions , the minisci heterocycle 
 c  h alkylation , and radical - based 
 cross - coupling chemistry . the ingenious barton 
 decarboxylation and deoxygenation ( barton  mccombie ) reactions 
 were invented as a consequence of an interaction barton had during 
 a consulting visit to schering - plough . methodic kinetic investigations by walling , beckwith , and ingold , among others , demonstrated the remarkable 
 selectivity of radicals , thus propelling significant developments 
 in synthetic radical chemistry in the 1980s . authoritative 
 treatise on the rules for radical ring 
 closure set the stage for the ueno curran s 
 stunning achievements in total synthesis illustrate the innate ability 
 of radical chain reactions to effect tandem bond formations . others provided absolute rate constants for 
 numerous radical processes ( a small sampling of rate data is shown in figure 1b ) . the scope of radical precursors was appreciably expanded toward 
 the end of the 1980s . zard s startling xanthate transfer 
 chemistry found applications in both polymerization and organic synthesis . use 
 of pet , nugent and rajanbabu s epoxide reduction , and mukaiyama s use of in situ - generated metal hydride species 
 opened the door to using ubiquitous functionalities such as carboxylates , 
 epoxides , and olefins as radical precursors . significant advances 
 were made in multiple directions shortly before 
 the advent of the 21st century . the development of atom - transfer radical 
 polymerization ( atrp ) in the 1990s led to countless applications in 
 material science . pioneering efforts 
 by curran , giese , porter , sibi , and renaud furnished elegant methods 
 of stereocontrolled radical additions ( depicted in figure 1 is a simplified 
 representation of sibi s chiral lewis acid - mediated enantioselective 
 radical addition ) . roberts s enantioselective 
 hydrosilylation offered a complementary approach where a thiyl 
 radical is the source of chirality . chatgilialoglu s silane reagents , walton and studer s cyclohexadienes , and curran s fluorous stannanes represent practical means 
 of ameliorating the classical  tin hydride method  . studer s studies on nitroxyl radicals had tangible impacts 
 on both cyclization and polymerization reactions . radical - based azide transfer , emerging from renaud s 
 laboratory , forges c they have shown that radicals can be harnessed 
 in unique and exciting ways to deliver useful structures in an incredibly 
 rapid fashion . sometimes radicals have enabled access to chemical 
 space that was previously unimaginable , and in other cases their use 
 facilitates the most concise route to a target structure . more often 
 than not , embracing radical reactivity leads to unique applications 
 in an industrial setting . in our view , the properties of radicals and the reactions they enable 
 can have a profound impact in drug discovery , agrochemicals , material 
 science , and fine - chemical manufacturing . the next five sections highlight separate areas of radical chemistry 
 that our laboratory has been involved in over the past decade , followed 
 by a perspective on the latest developments in the field of radical 
 chemistry . it is our hope that some of the transformations highlighted 
 will find use by those making materials for the betterment of humankind . the hapalindole 
 family of marine natural products ( e.g. , 17 ) combines promising bioactivities 
 with startling structural complexity ( figure 2a ) . a retrosynthetic 
 analysis of these indole alkaloids , aiming to divergently access as many family members as possible , revealed 8 as a common precursor . the union of 
 indole and carvone ( 11 ) represented the most direct means 
 to access 8 . however , the electron - rich indole is affixed 
 at c-3 to the -carbon of a ketone , creating a notoriously challenging 
 dissonant relationship which is usually surmounted in ionic chemistry 
 through reactivity umpolung . such an approach requires 
 extraneous functional group interconversions associated with prefunctionalized 
 building blocks such as 9 and 10 . evolution of enolate oxidative coupling in our laboratory 
 and its 
 synthetic applications . to avoid these concession steps while utilizing the inherent 
 reactivity 
 of these systems , a single - electron oxidation of enolates was pursued . it was envisaged that interactions between the in situ - formed electrophilic -keto radical and a 
 nucleophilic indole species would afford 8 ( putatively 
 via 12 and 13 ) . after some initial forays , 
 cu(ii ) 2-ethylhexanoate was found to effect the direct coupling between 
 indoles and enolate - derived -keto radicals ( figure 2b ) . as the reaction takes advantage 
 of the intrinsic nucleophilicity of indoles , coupling takes 
 place selectively at c-3 , and protection of the free n ample amounts of 8 were obtained in a single 
 step , allowing protecting - group - free syntheses of various hapalindole 
 alkaloids . the chemoselectivity of this process is notable , 
 with various sensitive functionalities such as epoxides , halides , 
 and alcohols being well tolerated . enolates 
 of esters and amides can be used as well ; this allows introduction 
 of chiral auxiliaries to furnish enantioenriched products . ma and co - workers beautifully extended this oxidative coupling 
 approach even when the c-3 position of indole was substituted , allowing 
 them to expediently forge challenging quaternary centers en 
 route to ( )-communesin f ( 14 ) , ( )-vincorine 
 ( 15 ) , and n - methyl - decarbomethoxy - chanofruticosinate 
 ( 16 ) . unprotected 
 pyrroles ( 18 ) are also viable substrates 
 that react regioselectively at c-2 ( figure 2c ) : a four - step synthesis of ( s)-ketorolac ( 20 ) was developed on the basis of this 
 reactivity . notably , this anti - inflammatory 
 agent is currently administered in racemic form , even though the ( s)-enantiomer is known to exhibit fewer side effects . efforts were undertaken to explore the 
 radical chemistry of enolates 
 further . in the presence of an iron or copper oxidant , heterodimerization 
 between two enolates was achieved both intramolecularly and intermolecularly ( figure 2d ) . in the latter case , when enolates of amides or oxazolidines 
 ( 21 ) are reacted with those of esters or ketones ( 22 ) , differences in redox potentials are sufficiently large , 
 and heterodimerization products such as 23a  c are formed exclusively . this reaction furnishes 1,4-dicarbonyl 
 products ( 23 ) with the concomitant creation of two vicinal 
 stereocenters in a redox - economical fashion . the heterocoupling reaction thus permitted short syntheses of 
 a metalloproteinase inhibitor ( 24 ) and the natural product bursehernin ( 25 ) ; the intramolecular 
 variant was harnessed to forge highly congested c c bonds in 
 our syntheses of ( + ) -stephacidin a ( 26 ) and ( + ) -avrainvillamide 
 ( 27 ) , as well as ( )-stephacidin b ( 28 ) ( figure 2e ) . moreover , oxidative enolate heterocoupling has 
 found use in both industrial and academic circles . for instance , gavai 
 and co - workers from bristol - myers squibb used this method to synthesize 
 a series of anticancer agents such as bms-906024 ( 29 ) 
 ( currently in phase ii clinical trials ) . the groups of overman , tang , nicolaou , yang , and thomson have applied 
 this approach to the syntheses of ( )-actinophyllic acid 
 ( 30 ) , spirobacillene a ( 31 ) , furanocembranoid 
 precursors such as 32 , ( + ) -propindilactone g ( 33 ) , and metacycloprodigiosin ( 34 ) , and 
 propolisbenzofuran b ( 35 ) , respectively . our interest in silver - mediated 
 radical reactions originated from 
 the total syntheses of the axinellamines ( 38 ) , massidine , and 
 palauamine ( figure 3 ) . imidazole 
 alkaloids each possess a dense array of nitrogenous functionalities , 
 among which the common guanidinium hemiaminal motif stands 
 out as a vexing feature . to avert concessional maneuvers , the installation 
 of this sensitive moiety was deferred to a late stage via a direct 
 oxidation of c-20 . this strategy would simultaneously allow for the 
 synthesis of the entire alkaloid family from a common intermediate . after extensive experimentation , silver(ii ) picolinate was identified 
 as the optimal oxidant for this unique transformation ( 36  37 ) ( figure 3a ) . strikingly , the c-20 position was oxidized with 
 admirable chemo- and regioselectivity , delivering the hemiaminal 
 without over - oxidation . this enabling reaction not only led to 
 the total syntheses of the axinellamines , massidine , and palauamine 
 but also allowed us to procure axinellamines in gram quantities 
 to establish their broad - spectrum anti - bacterial activities . 14783 - 00 - 7 ) has now been commercialized by sigma - aldrich , the 
 initial scope of this reaction is currently limited to the esoteric 
 area of guanidine oxidation . we were 
 thus motivated to look into other silver - catalyzed processes with 
 more translational potential . the venerable minisci reaction 
 is one such example wherein a carboxylic 
 acid undergoes radical decarboxylation in the presence of a 
 silver catalyst . the alkyl radical thus 
 formed can directly functionalize electron - deficient heteroarenes 
 ( 39 ) . the importance of these omnipresent heteroarenes 
 can not be overstated  they are vital to life and are found in 
 vitamins , drugs , dyes , pesticides , and polymers . despite the tremendous amount of work describing their 
 functionalizations , societal needs call for more - efficient syntheses 
 of ( hetero)biaryl frameworks to access various pharmaceutical core 
 structures , as well as the simple stitching of small alkyl groups 
 for the modulation of physiochemical properties . such transformations are often achieved by  programmed  
 or regiospecific chemistry ( figure 3b ) . although predictable and programmable 
 methods will continue to be vital in all aspects of chemistry , the 
 method 39  40  41 inherently requires two steps or more . as chemists are constantly 
 searching for rapid and operationally simple ways to generate a large 
 library of related compounds for screening , simple c  h functionalization 
 techniques are needed ( 39  41 ) to 
 directly access desired c although such one - step methods , 
 exemplified by directed hydrogen  metal exchange , already exist , they require cumbersome cryogenic , 
 anaerobic , or anhydrous conditions . with 
 the peculiar reactivity and selectivity of radicals , nevertheless , this classical 
 reaction presents several drawbacks which preclude its broad applications : 
 radical generation from the carboxylic acid is relatively inefficient 
 and limited in scope . consequently , elevated temperatures as well 
 as prolonged reaction times are often necessary . formation of aryl 
 radicals via decarboxylation is particularly challenging , and 
 heteroarene acceptors have to be used in super - stoichiometric 
 quantities to trap these fleeting species . this gap in methodology was addressed with the identification 
 of 
 aryl boronic acids as convenient radical progenitors . $ 380/mol ) and a persulfate oxidant can efficiently homolyze the 
 c  b bond under ambient temperature ( figure 3c ) . the resulting 
 radical was found to readily attack a variety of heteroarenes 
 in an aqueous medium , affording arylation products 42 following spontaneous re - aromatization . while triplet oxygen 
 is known to combine with radicals at diffusion rates , running the 
 reaction under open air did not diminish the yields , presumably because 
 the effective concentration of oxygen is low in the reaction system . the regiochemical course of the reaction is governed predictably 
 by the innate electron density of the heteroaryl substrates : 
 pyridines or quinolines are preferentially arylated at c-2 , and substrates 
 bearing multiple nitrogens such as pyrimidines , pyrazines , or quinoxalines 
 favor arylation at the most electron - deficient positions . this 
 diverse range of substrates encompasses many privileged medicinal 
 scaffolds , making the reaction amenable for drug derivatization . for 
 example , quinine can be functionalized selectively at its quinoline 
 core to furnish 42a in the presence of several other 
 unprotected functionalities , including a highly oxidizable benzylic 
 alcohol , an electron - rich olefin , and a basic quinuclidine nitrogen . many other functional groups , such as ketones and aryl halides , exhibited 
 compatibility with the mild reaction conditions . the exceptional chemoselectivity 
 of this radical process , coupled with its operational simplicity , 
 allows rapid diversification of densely functionalized active pharmaceutical 
 ingredients ( apis ) . in an analogous fashion , molander developed a 
 manganese - mediated heteroarene alkylation wherein radicals obtained 
 from his eponymous potassium trifluoroborates were found to 
 react with pyridines and quinolines , forming various adducts ( 43 ) . shortly before molander s 
 report , benzoquinone ( 44 ) was found to undergo 
 c  h alkylation under 
 borono - minisci conditions with alkyl boronic acids to give products 
 such as 45a , b ( figure 3d ) . like -deficient 
 heteroarenes , 44 also reacted smoothly with aryl 
 boronic acids of varying electron densities to afford 45c  f . benzoquinone adduct ( 45h ) was obtained without protecting the steroidal ketone ; a farnesyl 
 chain can be appended selectively at the terminal position ( 45 g ) . substituted quinones are viable substrates as well , 
 permitting schwalbe and co - workers to prepare the potent allergen 
 primin ( 46 ) in a single step . although quinones are prevalent motifs in biomedical and material 
 research , few general methods for their direct installations have 
 hitherto been developed . in fact , many of the quinone adducts surveyed 
 during the course of the reaction development represented new structural 
 entities . despite their semblance of 
 michael acceptors , quinones rarely undergo smooth conjugate additions 
 with organometallic reagents ; their 
 inertia toward transition metal catalysis is evidenced by their roles 
 as ligands or oxidants in such reactions . this simple chemical avenue , through a radical process , tames quinones 
 unique electronic properties . moreover , owing to the development of 
 the suzuki coupling , a multitude of boronic 
 acids are now available to medicinal chemistry practitioners . capitalizing 
 on the ubiquity of these radical precursors , the borono - minisci reaction 
 represents a unique opportunity to exploit the biomedical niches of 
 both quinones and heteroarenes in depth . b 
 bond - forming methods , from the pioneering efforts of h. c. brown to seminal studies on c  h borylation . the scope of this chemistry can thus be expanded 
 far beyond the commercial repertoire of boronic acids . simplifying 
 retrosynthetic disconnections can therefore be devised on the 
 basis of this innate c  h functionalization strategy . for instance , 
 a borono - minisci cyclization was conceived to construct polycyclic 
 scaffolds such as 48 from the corresponding boronic acid 
 derivative 47 , which can in turn be obtained from the 
 halide ( figure 3e ) . this method furnishes the central ring in dibenzofurans 
 and fluorenones while obviating the use of hazardous arenediazonium 
 salts employed in the classical pschorr reaction . capitalizing further on the borono - minisci transform , 
 a terpenyl 
 radical precursor ,  borono - sclareolide  ( 49 ) , was synthesized ( figure 3f ) . the radical derived from 49 reacted readily with benzoquinone ( 44 ) , permitting 
 a rapid synthesis of ( + ) -chromazonarol ( 50 ) , which diverged 
 further to provide access to various meroterpenoids in a concise 
 and scalable fashion . these sesquiterpenoids possess intriguing 
 bioactivities which remain largely untapped due to material supply 
 issues this joint effort with leo pharma has furnished ample quantities of 
 each product , enabling explorations into a large area of natural product 
 space . in a similar fashion , the borono - minisci reaction allowed 
 expedient 
 syntheses of various valuable molecular architectures . these include sarcodonin ( 51 ) and phellodonin , botryllazines a ( 52 ) and b , cytotoxic meriolin ( 53 ) , and photochromic compounds such as 54 , as well as the sodium channel inhibitor 55 . aside from the original 
 silver catalyst , in some of these studies , iron salts or thermolysis was found to initiate 
 radical formation , further bolstering the practicality of the reaction . the trifluoromethyl ( cf3 ) group , in particular , 
 is an excellent methyl bioisostere it imparts various 
 favorable physicochemical attributes , such as lipophilicity 
 and metabolic stability , to a lead target . ( hetero)arenes bearing cf3 groups constitute an indispensable 
 part of numerous important drugs , including celebrex ( celecoxib ) , 
 sustiva ( efavirenz ) , and prozac ( fluoxetine ) . effective means of trifluoromethylation 
 are thus vehemently sought by both academic and industrial scientists . although cf3 can be introduced by transition metal - catalyzed 
 approaches , such methods are often air- and water - sensitive and require 
 prefunctionalization . a robust and yet 
 operationally simple radical approach to c however , direct application of the borono - minisci 
 conditions with 
 various heteroarenes failed to yield any trifluoromethylation 
 product 56 ( figure 4a ) . after considerable 
 investigation , [ cf3so2]na , a reagent originally 
 utilized by langlois for the trifluoromethylation of phenols 
 and anilines , was discovered to effect the conversion of c  h 
 bonds into c cf3 bonds in the presence of a cheap 
 industrial oxidant , t - buooh ( tbhp ) . sensitive functional groups such as alcohols , amines , and 
 olefins are left unscathed . this is ideal for the functionalization 
 of biomedically relevant substrates such as deoxyuridine , leading 
 to trifluridine / viroptic ( 56a ) . the reaction proceeds 
 through the intermediacy of a highly reactive trifluoromethyl 
 radical , which readily engages a gamut of both electron - deficient 
 and electron - rich heteroarenes . the addition of this radical 
 onto an unactivated olefin was also observed in our initial report ; this precedent has subsequently been extended 
 in many creative ways . applying this 
 method , molinski and co - workers were able to selectively functionalize 
 the pyrrole ring of agelastatin . the resulting 13-trifluoromethylagelastatin ( 56b ) exhibited considerably higher potency against chronic 
 lymphocytic leukemia than the parent compound . overall , this 
 c  h functionalization protocol allows for the rapid late - stage 
 derivatization of existing drugs and known pharmaceutical motifs under 
 practical ( open - flask ) conditions . development and applications of sulfinate 
 reagents as enabling 
 radical precursors in biomedical research . the effectiveness of langlois s salt as a trifluoromethyl 
 radical precursor stems from its weak c  s bond ( figure 4a ) ; moreover , its propensity 
 to extrude so2 under oxidative conditions entropically 
 favors radical formation . in anticipation of the generality of these 
 properties , syntheses of various sulfinates were undertaken to access 
 a diverse array of carbon - centered radicals . during this process , choice of the cation was found to be critical : 
 while sodium fluoroalkanesulfinates often lack stability 
 or reactivity , the corresponding zinc salts proved superior . the first reagent of the series , zinc difluoromethanesulfinate , 
 or [ cf2h  so2]2zn ( dubbed  dfms  ) , 
 is an air - stable compound that allowed for c  h to c  cf2h transformation ( figure 4b ) . heteroarene 
 trifluoromethylation was revisited : [ cf3so2]2zn ( tfms ) was synthesized , and the yield - enhancing 
 zinc effect was observed . building on 
 this positive effect , a flurry of other zinc bis(fluoroalkane)sulfinate 
 reagents were synthesized ( only their chemical acronyms are shown 
 here ) . these reagents can modulate the physicochemical 
 profiles of various drug candidates through chemoselective radical 
 reactions : dfms installs the cf2h group , leading to phenol 
 bioisosteres ; dfes creates aryl ether isosteres ; psms draws inspirations 
 from nature s s - adenosyl methionine ( sam ) 
 methyl transferase to enable site - selective methylation . c  h 
 functionalization using these salts can be carried out in a variety 
 of biologically relevant media ( aqueous and aerobic ) , including cell 
 lysate , oolong tea , and a lactamase buffer ( figure 4b ) ! it is worth noting that sulfinate salts can also participate in 
 desulfinylative cross - couplings with boronic acid derivatives and 
 carboxylic acids . the sulfinate 
 reagents described above have been commercialized 
 by sigma - aldrich as diversinates ( catalog numbers are shown in figure 4b ) and have already 
 gained much popularity within the pharmaceutical community . high demand 
 for dfms has prompted large - scale industrial production , providing 
 commercial access to 1 kg bottles . as a testament to the impact of 
 this chemistry notably , roughly 80% of the purchases are made by pharmaceutical companies 
 such as bristol - myers squibb , novartis , merck , gilead , genentech , 
 roche , boehringer ingelheim , and pfizer . elaborating further 
 on this work , a linker reagent ( daas - na ) was 
 developed . this difluoroalkyl azide linker enables the bioconjugation 
 of heteroarene drugs to monoclonal antibodies ( figure 4b ) . typically , only conventional functional groups can be tagged 
 by linkers , but some medicinal scaffolds present the challenge of 
 not having any apparent chemical handles . the linker can be installed onto complex 
 drugs such as pioglitazone and bosutinib with admirable selectivity 
 to yield 58a and 58b . in another application 
 of sulfinate chemistry , dfms was used as 
 a litmus test to predict the vulnerability of a pharmaceutical candidate 
 toward aldehyde oxidase ( ao ) metabolism , which is thought to proceed 
 via the nucleophilic attack of a high - valent molybdenum species 
 onto a heteroarene s most electrophilic position . identifications of such positions are prohibitively 
 difficult in fused azaheterocyclic systems ; computational 
 modeling has also been largely ineffective . the nucleophilic difluoromethyl radical generated from 
 dfms acts as a rapid diagnostic for ao susceptibility , reacting with 
 electron - deficient heteroarenes that are prone to ao degradation 
 ( figure 4b ) . the addition 
 of a metabolically stable difluoromethyl motif into a position 
 prone to ao offered a potential inroad to a therapeutic agent . aside from the nucleophilic difluoromethyl radical , 
 ( fluoro)alkyl radicals of varying polarities can be accessed from 
 different sulfinate salts . these reagents can be harnessed as probes to elucidate the intrinsic 
 reactivities of heteroarenes . regiochemical 
 outcomes of such processes were unpredictable owing to the presence 
 of substituents exerting additive effects . the chemoselectivity 
 of sulfinate radical chemistry coupled with its robustness enabled 
 investigations into a large sampling of heteroarenes under various 
 conditions . as a result , a set of general guidelines was furnished 
 to predict the positional selectivity of heteroaromatic radical 
 c  h functionalizations ( figure 4c ) . these empirical rules 
 determine the most nucleophilic / electrophilic positions of a heteroarene 
 through the additive effects of various substituents . thus , site - specific 
 modification of complex drugs such as nevirapine can be formulated , 
 as addition of the nucleophilic isopropyl radical led exclusively 
 to 60 , in accordance with predicted selectivity . tandem 
 functionalization of dihydroquinine was realized with isopropyl 
 and trifluoromethyl radicals attacking the electrophilic 
 c-2 and nucleophilic c-7 sequentially to yield 61 . relative contributions of opposing 
 substituents were found to depend on external factors such as solvent 
 and ph  thus , the regiochemical outcome of certain substrates 
 can be fine - tuned through simple variations in reaction conditions . while in an acidic chloroform / water mixture the electrophilic 
 cf3 radical reacts with 62 selectively at 
 c-4 , use of dmso as solvent elicits  conjugate reactivity  
 of the ester group and c-5 substitution prevails . in cases where 
 large quantities of a product are needed , the use 
 of stoichiometric tbhp can be circumvented when electrochemistry 
 is used to initiate the desulfinylative radical formation . various recalcitrant substrates such as pentoxyfylline 
 ( 56c ) or metroindazole ( 56d ) showed 
 improved yields ( figure 4d ) ; monitoring of the reaction progress under electrochemical 
 initiation also allowed deconvolution of processes related to radical 
 formation and radical consumption . some sulfinate reagents ( 64 ) can be prepared 
 from 
 the corresponding sulfonyl chlorides ( 63 ) . however , only a limited number of these expensive starting materials 
 are commercially available . the hu reagent 
 ( 65 ) represents an alternative precursor with the pyridylsulfone 
 moiety serving as a sulfinate surrogate . this route , nevertheless , can 
 only furnish difluoroalkyl sulfinates ( 67 ) ( figure 4e ) . in an effort 
 to generate a larger repertoire of sulfinates , an interrupted  
 barton decarboxylation was developed , 
 converting carboxylic acids 68 , which are inexpensive 
 chemical feedstock building blocks ( vide infra ) , 
 to sulfinates in good yields ( figure 4f ) . this is achieved 
 through sequential barton ester ( 69 ) formation with inexpensive n - hydroxy-2-thiopyridone salts ( industrial feedstock ) 
 and photolytic rearrangement ( 69  70 ) . carboxylic acids are often not convenient precursors of reactive radical 
 species but can now be easily converted into  designer sulfinates ( 71 ) , which are efficient radical precursors . 
 following this simplifying transform , an assortment of sulfinates 
 of medicinal relevance has been synthesized ( e.g. , 71a these reagents granted rapid access to heteroarene 
 derivatives that would otherwise require laborious de novo preparations . for example , the previous synthesis of 74 was achieved in four steps from a starting material of limited availability , 
 enlisting the use of hazardous diazomethane to append the coveted 
 trifluorocyclopropyl motif over the course of 1 week . tfcs ( 71a ) , on the other hand , 
 allows the installation of trifluorocyclopropyl directly to 
 afford the same product after a two - step , one - pot operation in about 
 2 h. as with other sulfinates , these reagents have the ability to 
 change the physicochemical and biological properties of the 
 parent molecule to impact various aspects of drug discovery , including 
 lead target modification , bioisostere formation , and bioconjugation . as with both the oxidative enolate 
 coupling and the borono - minisci 
 reaction , the development 
 of iron - mediated radical olefin hydrofunctionalizations 
 in our laboratory can be traced back to natural product synthesis , 
 specifically from the ent - kaurane family of terpenes . adhering to the two - phase paradigm of terpene 
 synthesis required access to 77 ( figure 5a ) as a cyclase phase end point . while terpene skeletons have frequently been 
 constructed using cationic polyene cyclizations , the use of radical methodologies in terpene synthesis has 
 largely been limited to the pioneering work of the snider group . it was our hope to develop a complementary 
 radical - based method to forge lowly oxidized terpene frameworks ( 79  78  77 ) . the 
 pioneering metal - catalyzed olefin hydrofunctionalization approaches 
 of mukaiyama , carreira , boger , and others were particularly path - pointing in this regard . we envisioned that this type of reactivity could be coupled to a giese - type 
 radical conjugate addition to create a reductive olefin coupling between 
 an unactivated olefin and an electron - deficient olefin . n 
 bond construction . using boger s 
 iron - promoted olefin hydrofunctionalization 
 conditions as a starting point , we eventually 
 found that fe(acac)3 and phsih3 were able to 
 facilitate the desired transformation , where an unactivated donor 
 olefin 80 ( figure 5b , x = alkyl or aryl ) was able to be directly coupled to an 
 electron - deficient acceptor olefin ( 82 ) through the intermediacy 
 of nucleophilic radical 81 . the reaction can be applied to both intermolecular 
 cross - couplings and intramolecular cyclizations and could form 
 quaternary centers ( e.g. , 83b ) with ease . although 
 the donor scope was somewhat limited in our initial report , 
 the acceptor scope was quite broad , with almost any electron - withdrawing 
 group being competent to activate the acceptor olefin . upon further 
 investigation , we found that modifying the reaction conditions and 
 switching from fe(acac)3 to a slightly bulkier catalyst , 
 fe(dibm)3 , greatly expanded the reaction scope with regard 
 to the donor olefin . oxygen- , nitrogen- , 
 sulfur- , silicon- , boron- , and halogen - based functionalities could 
 all be tolerated to give products such as 83a , c  g . functionalized olefin cross - coupling allowed 
 for the execution of the synthesis of glucal derivative 83a in a single step from benzyl - protected 80a and methyl 
 vinyl ketone ( 82a ) and in a higher overall yield than 
 the three - step process that has previously been described in the literature . similar to the case of oxidative enolate 
 coupling , functionalized 
 olefin cross - coupling represents an umpolung of traditional reactivity 
 in the case of oxygen- and nitrogen - substituted donor olefins . the generation of the nucleophilic radical 
 takes place adjacent to the heteroatom , a site that is conventionally 
 electrophilic . the radical - based nature of this reaction is 
 perhaps its main benefit , as its orthogonality to polar and pd - based 
 cross - coupling chemistry allows it to tolerate functionalities that 
 are traditionally viewed as reactive . inspired by reports of 
 radical additions into hydrazones , we 
 wondered if the fe(acac)3/phsih3 system would 
 allow for a coupling of olefins with hydrazones . reaction with the hydrazone derived from formaldehyde 
 ( 85 ) would generate adduct 86 ( figure 5c ) . however , the 
 real utility would be in eliminating n2 and rso2h from 86 to generate 87 , the product of 
 a net addition of methane across an unactivated olefin . although this 
 is a conceptually simple transformation , there have only been scattered 
 reports in the literature , and a general strategy for olefin hydromethylation 
 did not exist . attempts to isolate 85 for use in an olefin hydromethylation 
 were unsuccessful ; however , preparing the hydrazone in situ allowed the realization of a hydromethylation sequence . mono- , 
 di- , and trisubstituted olefins could all be utilized , and due to 
 the radical nature of the reaction , free alcohols , halides , pseudohalides , 
 azides , and boronic esters could all be tolerated . this formal addition 
 of methane across an olefin could also be used to introduce isotopically 
 labeled methyl groups into molecules . by using different combinations 
 of deuterated and undeuterated formaldehyde and methanol , one can 
 incorporate any number of deuterium atoms into the methyl group ( 87a  d ) . the late - stage introduction of 
 a methyl group , or  methyl editing  , of natural product 
 scaffolds was demonstrated by employing -d - glucofuranose 
 derivatives citronellol , quinine , and gibberellic acid to give 87e  h , respectively . although the 
 transformations previously described enlisted carbon - based 
 electrophiles as coupling partners , it was discovered that non - carbon 
 electrophiles could also be used . when the olefin - to - nucleophilic 
 radical transformation ( 84  88 ) 
 was performed in the presence of nitro(hetero)arene ( 90 ) , hydroamination ( 89 ) was observed ( figure 5d ) . such a coupling was unexpected , as nitro(hetero)arenes 
 have largely been limited to the realm of nucleophilic aromatic 
 substitution and reduction to the corresponding anilines . however , 
 control studies provided evidence that the nitro functionality was 
 first reduced to the nitroso analogue 91 . as nitroso(hetero)arenes 
 are well - documented radical acceptors , it is likely that they serve 
 as the true electrophile in the olefin hydroamination . the scope of the hydroamination was shown 
 to be quite broad owing to the orthogonality that radical processes 
 have to traditional ionic reactivity . over 100 adducts were synthesized 
 using this methodology , with a host of functionalities present in 
 both the donor olefin and the nitro(hetero)arene scaffold . the 
 utilization of this method at both bristol - myers squibb and 
 kemxtree attests to the translational potential of this transformation . furthermore , it was found that the olefin hydroamination could 
 be used to accelerate the synthesis of a variety of medicinally relevant 
 molecules such as the glucocorticoid receptor modulator 89a . what previously took two steps to make from the nitrobenzopyrazole 90a and aziridine 93 could be achieved in a single 
 step in over twice the yield by using the same nitroheteroarene 
 to hydroaminate the disubstituted olefin 92 . two 
 other examples of utilizing the olefin hydroamination to abbreviate 
 the synthesis of medicinally relevant molecules were also presented . this reductive olefin coupling 
 has been utilized by other research 
 groups to achieve transformations that would have been difficult to 
 achieve otherwise . in an elegant approach to emindole sb ( 95 , figure 5e ) , pronin 
 was able to smoothly cyclize enal 94 with fe(acac)3 and phsih2(oi - pr ) to give the 
 natural product after additional elaboration . furthermore , olefin cross - coupling enabled chemists at 
 astrazeneca to circumvent an issue with the selective deoxygenation 
 of 98 by instead directly coupling the -branched 
 styrene 96 with enones to give diaryl ketone 97 ( figure 5f ) . in a report detailing a transfer hydrocyanation , 
 morandi and co - workers 
 realized that their newly developed method could be used in conjunction 
 with the reductive olefin coupling to effect the addition of ethylene 
 across an unactivated olefin . to demonstrate 
 this , estrone derivative 99 ( figure 5 g ) transfer hydrocyanation to norbornadiene 
 resulted in concomitant formation of the vinyl group of 101 in 78% yield over two steps . the scope of the electrophilic 
 coupling partners in these transformations 
 has recently been expanded by other groups . cui has shown that stabilized 
 diazo compounds ( 102 ) , -nitrostyrenes ( 104 ) , and para - quinone methides ( 106 ) could be used to generate hydrazones ( 103 ) , styrenes ( 105 ) , and phenols ( 107 ) respectively , when used to intercept the nucleophilic radical 
 intermediate ( figure 5h ) . furthermore , fu and co - workers demonstrated that the radical 
 conjugate addition into michael acceptors bearing evans oxazolidinones 
 ( 108 ) could serve as a useful pathway to access a variety 
 of protected -amino acids ( 109 ) with high diastereocontrol . although our foray into this area was 
 propelled with vague mechanistic 
 hypotheses suggesting that a radical intermediate is involved , shenvi 
 has recently shown that these reactions proceed through radical hydrogen 
 atom transfer ( hat ) processes , presumably through an in situ - generated transition metal hydride . further understanding of this mechanism will undoubtedly contribute 
 to the invention of even more creative ways to utilize olefins as 
 nucleophilic radical progenitors . the minisci decarboxylative 
 alkylation of heteroarenes is 
 an incredibly useful tool ( vide supra ) . one notable 
 drawback of this classical reaction is its reliance on the inherent 
 reactivity of heteroarenes with the scope generally limited to electron - deficient 
 systems . experience in this area coupled with the use of the barton 
 decarboxylation to prepare sulfinate salts ( 110  113 ) led us to 
 wonder if the experimental simplicity of minisci / barton chemistry 
 could be combined with the programmability of single - electron transfer 
 ( set ) cross - coupling catalyzed by ni or fe salts . part of the attractiveness of minisci chemistry is its use of feedstock 
 carboxylic acids whereas most set - based alkyl cross - couplings use 
 alkyl halides , which often need to be prepared . alkyl radicals generated 
 from barton esters ( e.g. , 110 ) are typically trapped 
 with a hydrogen - atom source ( e.g. , bu3snh ) or a variety 
 of other radical acceptors including 
 protonated electron - deficient heterocycles , but to our knowledge , had never been captured by a transition metal 
 for the purposes of cross - coupling ( figure 6a ) . development of redox - active esters ( raes ) as radical precursors 
 in cross - coupling reactions . to our delight , ni complex ( 1.0 equiv ) gave the 
 desired cross - coupling product ( 115 ) in 51% yield . however , 115 was still produced in 54% yield in the absence of light 
 at room temperature ! given that barton esters have , for 4 decades , 
 been known to give rise to radicals using either heat or light , it 
 was quite shocking that the same process could be mediated by a transition 
 metal . we hypothesized that the success of this reaction hinged on 
 the ability of the ligated ar  ni complex to reduce the barton 
 ester to a radical anion ( 114 ) that could then fragment 
 and decarboxylate , thereby generating an alkyl radical that recombines 
 with the ar ni complex followed by reductive elimination to 
 yield the coupled product . while 
 ar  ni complexes can be conveniently obtained from 
 stable ni(ii ) complexes and organozinc , photosensitivity of barton 
 esters thwarted the direct generalization of this transformation ( 116e  117 ) . instead , it was surmised 
 that activated esters commonly used in peptide bond formation might 
 be similarly predisposed to accept an electron . indeed , carpino s 
 hobt and hoat esters ( 116c and 116d formed in situ using hbtu or hatu , respectively ) worked extremely 
 well . even nefkens and tesser s active 
 ester , n - hydroxyphthalimide ( nhpi , 116a ) , functioned smoothly in this reaction ( figure 6b ) . retrospectively , 
 okada s finding that nhpi esters could fragment under pet conditions 
 reinforced the feasibility of such reactions . the tetrachloro derivative of nhpi ( tcnhpi , 116b ) , 
 introduced into organic synthesis in the context of an electrochemical 
 c  h oxidation method , was also found to be a great substrate 
 for this type of coupling . however , 
 not all esters that can activate a carbonyl in amide - bond - forming 
 chemistry were competent . for example , n - hydroxysuccinimide 
 ( 118 ) or pentafluorophenyl groups ( 119 ) were not . thus , we define a redox - active ester ( rae ) as one that 
 can serve as a precursor to the corresponding radical under set conditions . 
 building upon the initial discovery , a catalytic variant was developed , 
 allowing for the coupling of secondary raes ( 116 ) with 
 arylzinc reagents using a simple ni salt . a striking feature of this reaction was that both -heteroatom - stabilized 
 carboxylic acids as well as simple unstabilized alkyl acids were competent 
 coupling partners in a simple , thermal process . it was hypothesized that raes could be thought of more 
 generally as a proxy or substitute for alkyl halides in set - based 
 cross - coupling chemistry . whereas the area of alkyl  aryl 
 cross - coupling is expansive , 
 the number of robust alkyl alkyl cross - couplings is comparatively 
 miniscule due to the difficulty associated with controlling such reactions . sp cross - coupling of raes with dialkylzinc reagents ( figure 6c ) performed so smoothly . a wide range of carboxylic acids were found 
 to be compatible , featuring multiple examples of carboxylic acid - containing 
 natural products ( e.g. , 122d ) , drug molecules ( e.g. , 122b ) , and bridgehead tertiary acids ( e.g. , 123 ) . as an alternative to traditional williamson ether synthesis , alkylation 
 of -oxy raes is presented in numerous examples such as 122e . it is significant that the multitude of carboxylic acid 
 substrates , variegated in nature , were all commercially available . the procedural simplicity is also notable as reactions were carried 
 out without a glovebox with ease comparable to that of classical amide 
 bond formation . although raes of simple tertiary acids ( e.g. , 
 pivalic acid ) are 
 not competent direct coupling partners with either aryl or alkylzinc 
 reagents , presumably due to steric constraints , a conjunctive coupling 
 between a tertiary rae ( 124 ) , radical trap ( such as benzyl 
 acrylate ) , and an arylzinc reagent was envisioned , thereby exploiting 
 this perceived limitation ( figure 6d ) . reasoning that a tertiary radical 
 would react rapidly with an acrylate in a 1,4-fashion as we demonstrated 
 in our fe - based studies ( vide supra ) , it was logical 
 that the resulting -keto radical would recombine with an ar ni 
 complex and reductively eliminate , thereby forging two c  c 
 bonds and generating a quaternary center in a single reaction . this 
 scalable three - component coupling rapidly generates structures ( 125a  g ) that would be exceedingly difficult 
 to access through traditional ionic chemistry in moderate to good 
 yields . the analogy of this chemistry to amide bond formation 
 really only 
 holds if it exhibits the necessary chemoselectivity to operate 
 in the context of solid - phase peptide synthesis . this was demonstrated 
 in several instances , the most notable of which is the simultaneous 
 sp  sp cross - coupling of both aspartic 
 acid and glutamic acid side chains on a resin - bound peptide ( figure 6e ) . this transformation 
 allows for the synthesis of highly diverse functionalized peptides 
 containing non - proteinogenic amino acids such as 127 . although initial reports focused on the use of organozinc reagents 
 in rae cross - couplings , attention rapidly turned to the use of boronic 
 acids due to their shelf stability and wide availability ( vide supra ) . boronic acids , like carboxylic acids , are among 
 the most widely commercially available building blocks and are often 
 used by medicinal chemists to generate diversity in a short , timely 
 manner . after extensive optimization , this desirable transformation 
 was realized using cheap nicl26h2o as 
 a ni precatalyst and triethylamine as an inexpensive base ( figure 6f ) . interestingly , this cross - coupling relied on the exclusive 
 use of the tcnhpi rae ( nhpi and other raes explored did not work ) . 
 a wide range of both aryl ( 129a  c , e , f ) and styrenyl ( 129d ) 
 boronic acids , including heteroaromatic ones ( 129a , b , e ) , can be coupled using this chemistry , and 
 this reaction shows remarkable chemoselectivity : aryl bromides 
 on the boronic acid coupling partner are tolerated ( 129c , f ) and primary alkyl bromides ( 129f ) present 
 on primary raes remain intact under the reaction conditions , thereby 
 showing orthogonality to other alkyl - suzuki - type arylation reactions . as the component 
 of the method was of utmost importance to us , it was also shown that 
 the reaction requires no special precautions to exclude moisture or 
 air , making the barrier to adoption in a discovery setting quite low . as mentioned above , raes represent a unique way of converting an 
 alkyl carboxylic acid to the functional equivalent of an alkyl halide . 
 for this to be proven as generally true , other transition metal catalysts 
 capable of set - type coupling should work as well . the first choice 
 for exploration in this regard was fe - based catalysis due to its numerous 
 advertised benefits over ni , such as its lack of toxicity and wide 
 abundance . yet , we sought more than just an alternative to ni for 
 the same reaction . in an extensive study , the use of ni- and fe - based 
 catalysts was benchmarked across a range of over 40 substrates ( e.g. , 130a , b ) to understand the context - dependent advantages 
 of each ( figure 6 g ) . for the fe - system , a catalyst / ligand combination 
 that was pioneered by nakamura and bedford for the analogous alkyl 
 halides was employed . the findings were surprising 
 in that fe catalysis enabled near - instantaneous reaction rates , applicability 
 to tertiary systems ( 124 ) including access to exotic 
 cubane structures ( 131  132 ) , and 
 superiority in the coupling of amino acid and unactivated primary 
 systems ( figure 6h ) . 
 combined with the obvious advantages of fe over ni , this reaction 
 may prove to be useful not only in a discovery setting but also in 
 the demanding area of process chemistry . ni- and fe - catalyzed 
 rae cross - coupling presumably operates under 
 mechanisms analogous to those previously reported in the literature 
 for ni- and fe - catalyzed cross - couplings ( figure 6i ) of alkyl halides . a low - valent fe or ni 
 complex likely undergoes transmetalation with an organometallic reagent 
 ( 133  134 ) . set from 134 to the rae ( 124 ) generates a radical anion ( 137 ) that undergoes decarboxylative fragmentation to generate an alkyl 
 radical ( 138 ) . this alkyl radical then recombines with 
 the metal center to form 136 ( high selectivity of this 
 heterocoupling process over homodimerization of 138 can 
 be attributed to the pre , vide infra ) . the presence of radical intermediates in all of these 
 transformations has been implicated in radical cyclopropane ring - opening 
 experiments . further mechanistic studies are underway to understand 
 the role of ligands , stoichiometry , and rae structure on reactivity . concurrent with our initial studies , weix and co - workers demonstrated 
 the viability of raes in ni - catalyzed cross - electrophile couplings 
 and found that aryl iodides as well as acid chlorides can be coupled 
 to raes under ni catalysis ( figure 6j ) . inspired by our work , 
 others have adapted raes for additional ni - catalyzed transformations . judging by the hundreds of different known 
 reactions of alkyl halides in set - based cross - couplings , it is anticipated 
 that raes will find wide use and permit a broad array of carboxylic 
 acid building blocks to be enlisted in similar transformations . they are generally inert 
 to a host of reactive functionalities such as amines and alcohols . thus , radical reactions can often be carried out on complex substrates 
 in open flasks . radicals frequently enable the most direct means of 
 reactivity umpolung . due to their early transition states and lack 
 of stifling aggregation spheres , these properties , in our view , make 
 them eminent candidates to either provide a shortcut to known molecular 
 frameworks or to open up new chemical space altogether . inspiring 
 recent accomplishments , primarily from other laboratories , 
 that may guide future directions of this vibrant discipline are organized 
 into the following five sections : ( 1 ) unique reactivity that is also 
 scalable ( figure 7a ) , 
 ( 2 ) rapid generation of complexity in total synthesis ( figure 7b ) , ( 3 ) chemo- and regioselective 
 transformations ( figure 7c ) , ( 4 ) cross - coupling chemistry ( figure 7d ) , and ( 5 ) enantioselective radical 
 reactions ( figure 7e ) . radical chemistry : selected highlights from the past 5 years that 
 capitalize on the unique power of these reactive intermediates . mild and robust radical reactions 
 have found numerous applications 
 ( figure 7a ) . this manganese - mediated reaction proceeds through 
 the intermediacy of a benzylic radical and is complete within several 
 minutes , allowing efficient radiolabeling of drug molecules such as 
 enalaprilat with f to afford 139 . a similar 
 radical c  h fluorination was utilized by merck to furnish -fluoroleucine 
 methyl ester ( 140 ) en route to odanacatib ; this protocol , based on polyoxometalate pet 
 chemistry originating in the 1990s , was 
 amenable to process scale in a continuous flow reactor . in another elegant masterpiece of process development , such efforts to harness radicals on a large 
 scale are espoused by milder and more sustainable means of radical 
 generation . in an illustrative example , electrochemistry was used to initiate a radical cationic cyclization , 
 delivering diazonamide analogue dz-2384 ( 142 ) on a large 
 scale ; skeletons of complex terpenes 
 could also be oxidized electrochemically in an environmentally benign 
 fashion to furnish enones such as 143 . meanwhile , potassium tert - butoxide was 
 found to promote c  h silylation via a putative radical 
 species . this inexpensive and scalable 
 reaction developed by stoltz and grubbs gives rapid access to silylated 
 drug analogues such as 144 , boding well for industrial 
 applications . radicals have continued to play vital roles in 
 the syntheses of 
 complex molecules ( figure 7b ) . while the ability of free radicals to propagate in chain 
 reactions have always been exploited to forge multiple bonds simultaneously , 
 increased mechanistic understanding of such processes enabled fine - tuning 
 of selectivity , affording complexity in a controllable fashion . maimone s stunning synthesis of ( )-6-epi - ophiobolin n ( 145 ) embodies this notion : not only did 
 a radical cascade furnish the challenging skeleton in a single operation , 
 the use of a thiol catalyst overrode inherent conformational bias 
 to achieve the desired stereochemical outcome . in their syntheses of ( + ) -pleuromutilin ( 146 ) and ( )-maoecrystal z ( 147 ) , procter and reisman both 
 made use of samarium iodide mediated 
 radical cascades ; these reactions expediently stitch together ubiquitous 
 olefins and carbonyls . overman s synthesis of ( )-aplyviolene 
 ( 148 ) highlights radicals abilities to prevail 
 against steric crowding , as a strategic radical conjugate addition 
 was enlisted for the convergent union of two complex fragments . snyder s synthesis of ( + ) -scholarisine ( 149 ) 
 reinforced this point  a quaternary center is constructed via 
 a tandem radical translocation  cyclization . the affinity of radicals for peroxo species makes 
 them ideal candidates 
 for the rapid incorporation of oxygenated functionalities as well . this is evidenced through maimone s synthesis of ( + ) -cardamom 
 peroxide ( 150 ) wherein three c  o bonds are formed 
 in a single step . oxidative radical 
 cascades also permit the simultaneous construction of c  o and 
 c  c bonds as can be illustrated by the syntheses of clavilactone 
 a ( 151 ) and ( + ) -fusarisetin 
 a ( 152 ) by li and theodorakis , 
 respectively . the utility of radical cyclizations transcends 
 the realm of natural 
 products  alabugin and co - workers , for example , employed a reductive 
 radical cascade to prepare polyaromatic nanoribbons such as 153 ; this remarkable reaction accomplished five cyclizations , 
 tremendously expediting their synthetic endeavor . zard s bidirectional ketone synthesis convergently 
 merges unactivated olefins through a simple conjunctive radical precursor , 
 offering an alternative retrosynthetic strategy to a diverse range 
 of building blocks such as 154 . chemo- and regioselective radical methodologies have 
 continued 
 to flourish ( figure 7c ) . recent research has seen a renewed interest in the use of radicals 
 to activate c  h bonds . as has been reviewed extensively , such 
 an approach allows selective functionalization of unactivated c for instance , in their collaborative synthesis 
 of ( + ) -chlorolissoimide ( 155 ) , alexanian and vanderwal 
 took advantage of an intermolecular hlf reaction to directly effect 
 regioselective c h chlorination on ( + ) -sclareolide . while a halogenated amine derivative ( a chloroamide ) 
 was used to initiate c h abstraction as in the case of traditional 
 hlf protocols , betley and co - workers demonstrated that simple azides are capable of similar reactivities . when treated with an iron complex , alkyl azides were transformed into 
 cyclization products such as 156 via a radical pathway . in another variant of this classical reaction , 
 yu and co - workers achieved a tandem c h functionalization whereby 
 the lactam and olefin in 157 were forged in a single 
 step through consecutive c  h homolysis . through such processes , methods of intermolecular 
 c these reactions 
 enlist copper and iron catalysts to generate highly reactive radical 
 species from selectfluor and zhdankin s reagent ; in spite of their high energy , the ensuing 
 radicals exhibited strikingly high selectivity toward complex substrates 
 adorned with multiple functionalities  products such as 158 and 159 are obtained in synthetically useful 
 yields . s inspiring work on vinblastine analogues 
 ( 160 ) is another testament to the unparalleled chemoselectivity 
 of free radical processes . a late - stage hydroazidation 
 was utilized , where a tertiary radical was formed from an olefin via 
 hat ( vide supra ) . azidation of this intermediate 
 forged the final c  n bond in the presence of multiple functionalities . notably , the scope of such hat - based methodology is expanding as novel 
 hydrogen atom donors of varying selectivity profiles are being developed . curran s work on nhc - boranes provides an illustrative example 
 whereby these complexes could selectively reduce alkyl halides in 
 the presence of a labile epoxide to give 161 . on top of carbon - centered radicals , the 
 distinctive characteristics 
 of radical chemistry highlighted above pertain to a variety of other 
 species . n - centered ( sulfonyl)imidyl 
 radicals showed high reactivity and selectivity in their interactions 
 with bioactive heteroarenes and functional polyaromatics to afford 
 adducts such as 162 and 163 . these radicals 
 can be unleashed from bench - stable precursors through metal - mediated 
 or photoinduced cleavage of n - heteroatom bonds . the oxygen - centered diradical derived from decomposition of phthaloyl 
 peroxide was found to selectively react with arenes , affording complex 
 phenols such as 164 while sparing various reactive aliphatic 
 c  h bonds . the peculiar selectivity 
 can be explained by a reverse rebound mechanism . another emerging 
 approach to arene functionalization exploits the 
 high electrophilicity of aromatic radical cations . these transient species can be obtained electrochemically or through photoinduced or transition - metal - mediated electron transfer , as shown by the groups of yoshida , nicewicz , 
 and ritter , respectively . in each case , 
 arenes were selectively oxidized into the radical cations , leaving 
 different functionalities unscathed . regioselective trapping 
 by nitrogen - centered nucleophiles formed amination products such as 165 , 166 , and 167 . cross - coupling 
 reactions represent yet another exciting avenue 
 in recent radical research . building upon kochi s illuminating 
 legacy , empowering synergy between radicals and metal complexes through 
 the pre ( vide infra ) has significantly expanded the 
 scope of cross - coupling . through radical 
 reactivity , fu and co - workers demonstrated the challenging coupling 
 of unactivated tertiary halides with boronic acid derivatives ( figure 7d ) . nickel s propensity to undergo set was harnessed 
 to generate carbon - centered radicals , overcoming hindered halides 
 inertia toward two - electron oxidative additions . quaternary centers 
 as in the case of 168 can be constructed . in a similar 
 vein , molander designed a single - electron transmetalation process 
 wherein alkyl trifluoroborates were homolyzed under pet conditions , 
 and the resulting benzyl radical engaged in nickel - mediated coupling . products such as 169 , which are 
 difficult to access via classical suzuki coupling , can be obtained . radicals derived from stabilized carboxylic acids through pet undergo 
 similar nickel - catalyzed reactions . single - electron processes involving radicals have also been harnessed 
 to aid challenging c n coupling reactions . through photoinduced 
 phenyl radical generation , fu and peters developed ullmann - type couplings 
 of various nucleophiles . this 
 approach led to aryl amines such as 170 under mild conditions , 
 obviating the need for prolonged heating . n coupling of 
 unactivated secondary and tertiary halides using set - initiated radical 
 formation , affording hindered amine derivates such as 171 . alkyl radicals derived from hunsdiecker - type 
 reactions were also shown to undergo copper - mediated c an important ramification of this metal  radical 
 synergy 
 is the possibility of conducting enantioselective radical reactions 
 with chiral metal complexes . to this end , buchwald elegantly showcased 
 a convenient method to access enantioenriched butyrolactones 
 ( 173 ) via copper - mediated enantioselective cyclization . it is noteworthy that this reaction may be 
 initiated by a broad range of radical species . chiral copper catalyst 
 also allowed stahl and liu to achieve enantioselective benzylic 
 cyanation through a radical relay fu and macmillan synthesized chiral carbamates such as 175 , utilizing a chiral nickel catalyst to capture stabilized -amino 
 radicals derived from pet . weix and 
 co - workers reported that when the nugent  rajanbabu reaction was performed with a chiral titanium 
 complex , the resulting radical could be intercepted with nickel in 
 an enantioselective coupling , leading to 176 . in 
 a different approach , drawing inspiration from roberts s precedent , maruoka and co - workers utilized a 
 chiral thiyl radical to mediate enantioselective tandem c  c 
 bond formation . thiyl radicals 
 predisposition to undergo reversible additions with olefins allowed 
 them to be used in catalytic quantities ( 3% ) , while the temporal incorporation 
 of chirality led to 177 in good enantiomeric excess . ingold pre undergirds a significant portion 
 of the chemistry highlighted in figure 7 and warrants further discussion . high selectivity in many radical processes seems baffling at first , 
 as most carbon - centered radicals are transient species ( rtra , figure 8) which are expected to recombine at diffusion rates before 
 engaging in any productive reactions . pre offers a means of suppressing 
 this  ultra - fast  self - destruction using persistent 
 radicals ( rper ) that have lower rates 
 of dimerization . when rtra and rper are formed at equal rates in a reaction , 
 incipient homocoupling of rtra quickly 
 depletes its concentration , leading to a buildup of rper . under steady - state conditions , this excess rper scavenges any rtra that is formed , thereby favoring cross - coupling products . revisiting 
 the persistent radical effect ( pre ) . this phenomenon underscores the photostability of vitamin 
 b12 : when the c  co bond in methylcobalamin 
 ( 178 ) is photolyzed , dimerization between the resulting 
 methyl radical 
 is kept minimal by the persistent co(ii ) complex 179 . instead , heterocoupling quenches the reactive methyl radicals 
 to regenerate the vitamin ( figure 8a ) in a degenerate pathway . this equilibrium 
 can be altered in the presence of a radical trap 
 whereby transient radicals derived from cobalamine mimics ( e.g. , 180 ) can engage in irreversible addition reactions ( 182  183 ) . since homodimerization of 182 is suppressed through pre and reversible heterocoupling 
 with 181 regenerates 180 , cyclization proceeds 
 cleanly as the only net reaction . the profound impact of pre 
 extends far beyond organocobalt 
 chemistry  it underlies the resurgent interests in radical - based 
 cross couplings . most paramagnetic metal complexes can be construed 
 as persistent radicals . in cross - coupling reactions , set between metal 
 catalysts and organic electrophiles ( halides or rae ) generates these 
 species ( 186 , m = ni(i ) , pd(i ) , cu(ii ) , etc . ) at equal 
 rates as transient carbon - centered radicals ( e.g. , 187 ) . owing to the pre , dimerization of 187 is disfavored , and recombination with the paramagnetic 
 metal occurs preferentially ( 186 + 187  188 ) . cross - coupling products can thus be selectively furnished 
 after the ensuing reductive elimination step ( 188  189 ) . aside from metal complexes , the barton photolysis 
 ( 190  194 , figure 8b ) provides an illustrative example . in this 
 case , the long - lived nitrite radical 191 allows translocation 
 of the alkoxy radical 192 to outcompete premature termination 
 via dimerization . pre also accounts for the selective coupling between 
 the resulting carbon - centered radical 193 with 192 to afford the final product 194 . in an analogous 
 fashion , pre is operative in many other radical - mediated c  h 
 functionalizations using haloamides , halogenated amines ( e.g. , 
 hlf , vide supra ) , or hypoiodites ( e.g. , surez 
 reaction ) . nitroxides , exemplified by 
 tempo ( 196 ) , constitute another important class of persistent 
 organic radicals . while their application in tandem cyclizations ( 195  198 ) is depicted in figure 8 , these highly stable radicals have also played pivotal roles in living 
 polymerization reactions . since 
 the focus of this perspective is on the area of small - molecule 
 chemistry , a detailed discussion of these radical polymerization reactions 
 is beyond the scope . despite this , the 
 collection of studies in this section remains a stunning testament 
 to the versatility of radical species . they enable rapid and practical 
 routes to complex molecules or new bond disconnections that would 
 have been unimaginable even a few years ago . hence , radicals can provide 
 an opportunity to consider radically different ways 
 of achieving new transformations or synthesis plans . progress in so many areas of societal need , from agrochemicals 
 to drugs , relies on advances in organic chemistry . a perfect storm 
 of shortened timelines , increased regulatory hurdles , and shrinking 
 ip space has created an ideal opportunity for synthesis to make a 
 real difference . , they can save chemists enormous amounts of time 
 and can access wide areas of unexplored chemical space . in fact , the studies originating from our laboratory outlined in 
 this perspective were born out of necessity : simplifying the synthesis 
 of complex natural products in many cases required the invention of powerful radical - based reactions . interactions with industry inspired our group to apply the aforementioned 
 advantages of radicals to areas of great need . looking forward , one 
 can anticipate exciting new frontiers enabled by radical chemistry , 
 such as asymmetric cross - couplings of unstabilized systems , regiocontrolled 
 minisci - type functionalizations , and programmed cross - couplings 
 of olefin - derived radicals . one thing 
 is clear : the translational potential of radicals is high , and it 
 has only just begun to be exploited .
this 
 perspective illustrates the defining characteristics of free 
 radical chemistry , beginning with its rich and storied history . 
 studies 
 from our laboratory are discussed along with recent developments emanating 
 from others in this burgeoning area . 
 the practicality and chemoselectivity 
 of radical reactions enable rapid access to molecules of relevance 
 to drug discovery , agrochemistry , material science , and other 
 disciplines . 
 thus , these reactive intermediates possess inherent translational 
 potential , as they can be widely used to expedite scientific endeavors 
 for the betterment of humankind .