Single Electron Transfer in Radical Ion and Radical-Mediated Organic,Materials and Polymer SynthesisNa Zhang,† Shampa R. Samanta,† Brad M. Rosen,‡ and Virgil Percec*,†
†Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,United States‡DuPont Titanium Technologies, Chestnut Run Plaza, Wilmington, Delaware 19805, United States
CONTENTS
1. Introduction B1.1. Background and Scope of the Review B
2. Fundamentals of Single Electron Transfer inOrganic Synthesis B2.1. Key Reactions and Mechanisms B
2.1.1. Definitions of SET, ISET, and OSET B2.1.2. Dissociative and Sticky Single Electron
Transfer D2.1.3. SET in Organic Reactions D2.1.4. Dissociative and Associative SET Pro-
cesses E2.1.5. Historical Evolution of the Definition of
Atom-Transfer and Chain-Transfer Re-actions F
2.1.6. Comparison between Chain Transferand Atom Transfer I
2.2. Classes of Electron Donors and Acceptors J2.2.1. Inorganic Electron Donors and Accept-
ors J2.2.2. Organic Electron Donors and Acceptors K2.2.3. Electrochemical L
2.3. Classes of SET Adducts L2.3.1. Radicals L2.3.2. Radical Anions M2.3.3. Radical Cations O2.3.4. Organometallic Adducts P
3. Reductive Chemistry P3.1. SET Reactions with Alkyl Halides P
3.1.1. The Barbier Reaction P3.1.2. The Grignard Reaction R3.1.3. Kagan−Molander SmI2 Reaction S3.1.4. SET Reactions of Perfluoroalkyl Halides U3.1.5. Wurtz Coupling AC
3.1.6. The Muller−Rochow Process for Cu0-Catalyzed Synthesis of Dichlorodime-thylsilane AD
3.1.7. The Preparation of Synthetic EstrogensLed to the Discovery of Condensationby Reductive Dehalogenation Mediatedby Metals AE
3.1.8. Reductive Dehalogenation of Alkyl Hal-ides Mediated by Zero-Valent Metals AF
3.1.9. Reductive Dehalogenation by RadicalAnions AG
Substitution BY3.5. Thermal- and Photoinduced SET Mediated
by Amine Donors CA3.5.1. Reductive Dehalogenation Reactions
Mediated by Amine Donors CB3.5.2. Cyclization Reactions Mediated by
Amine Donors CC3.5.3. Recent Progress on SET of Amines CD3.5.4. Organic Super Electron Donors CE3.5.5. LRP Mediated by Amines CF3.5.6. LRP Mediated by Amonium Iodides CG
4.2.1. Polymer Synthesis by Scholl Reaction CJ4.2.2. Living Anionic Polymerization of Styr-
ene Initiated by Electron Transfer CM5. Reactions Involving Both Reductive and Oxida-
tion Chemistry CM5.1. Organic Electrosynthesis CM5.2. SET of Enolates CN
5.2.1. Asymmetric and Symmetric OxidativeCoupling of Enols and Phenols Tempo-rarily in an Intramolecular Structure CQ
6. SET in the Formation and Cleavage of ProtectiveGroups CQ
7. Concluding Remarks CQAuthor Information CR
Corresponding Author CRNotes CRBiographies CR
Acknowledgments CSAbbreviations CSReferences CT
1. INTRODUCTION
1.1. Background and Scope of the Review
The mechanisms of most organic reactions are considered toproceed by two-electron transfer pathways, even though bothbiology and radical chemistry rely extensively on one-electrontransfer processes. Radicals generated by homolytic cleavage athigh temperature were traditionally employed in the industrialproduction of polymers and to a lesser extent in the synthesis oforganic molecules. The demand for synthetic rubber in theUnited States during the Second World War drove thedevelopment of polymer synthesis by radical polymerization.1
While stable radical cations and radical anions were knownsince the 19th century and electrochemistry relies on one-electron processes, only a relatively small group of organicreactions was considered to involve one-electron transferknown also as single electron transfer (SET) mechanismsuntil the Taube2 classification and Marcus3 theory broughtclarification in this field. While polymer synthesis by conven-tional radical polymerization continues to dominate thetechnological aspects of this area, electrochemistry, conductingorganic materials and polymers, organometallic and metal-promoted organic synthesis, electron transfer in biology,electron transfer catalysis, and many others topics have becomenearly independent research fields. Numerous specialized
books, book series, and reviews covering individual topicsfrom these almost unrelated disciplines are available.4 To ourknowledge, a single monograph published in 2001 provides anexception covering in five volumes developments in variousaspects of single electron transfer processes from organicchemistry, inorganic chemistry, organometallic chemistry, andsupramolecular chemistry to biology.4b The goal of this Reviewis to discuss the mechanisms and the applications in organicsynthesis, materials, supramolecular, and polymer synthesis ofmost organic reactions mediated by single electron transfer.Because this Review is addressed to synthetic chemists involvedin organic, materials, supramolecular, and polymer synthesis, aminimal description of the mechanism of single electrontransfer presented in simple terminology will be discussed inthe introductory part. Each reaction or class of reactions will bediscussed by starting with the original discovery publication,followed by a summary of all or most review articles publishedin the field, and a discussion of the mechanism(s) and of themost important methodologic and synthetic developmentssince the most recent review was published. A task like this canbe quite challenging, because to our knowledge no previousreview or book like this is available. Therefore, we apologize tothe authors that feel that we have nonintentionally orintentionally omitted from this Review their work. Becauseeach subtopic and reaction covers a different period, thesedetails will be available at the proper place of this Review.ATRP has been reviewed thoroughly over the years,5−7 and,therefore, we will not repeat it again in this Review except forseveral mechanistic issues. Although SET-LRP was lastreviewed only in 2009,8 this Review will mention only somerecent mechanistic and methodologic developments. Anupdated review of the 2009 review on SET-LRP would betoo large, outside the scope of this Review, and, therefore, it willnot be included here. A combination of SciFinder, ISI Web ofKnowledge, and cross-reference was used to cover the literatureup to the end of September 2013 with some updated literatureincorporated at the revision stage that was generated during thefirst week of March, 2014.
2. FUNDAMENTALS OF SINGLE ELECTRON TRANSFERIN ORGANIC SYNTHESIS
2.1. Key Reactions and Mechanisms
2.1.1. Definitions of SET, ISET, and OSET. The singleelectron transfer (SET) process, also known as electron transfer(ET), has a history in organic synthesis that dates back to 1834when Faraday reported the first preparation of organiccompounds at electrodes (Scheme 1).9
The application of SET in organic synthesis by Wurtz,10
Barbier,11 Sandmeyer,12 and others during the 19th century iswell documented. Since then, SET processes have attractedsubstantial interest in both chemistry and biology.3 It wasknown since the early 20th century that when colorless
electron-donor (D) and electron-acceptor (A) organicmolecules are brought into contact, they form a coloredelectron donor−acceptor (EDA) complex, also known as acharge transfer complex (CTC), with partial charge transfer orwith even one electron being transferred from the donor to theacceptor. The developments on the “isotopic exchangeexperiments” as well as the introduction of new instrumenta-tion to study rapid chemical reactions such as the stopped-flowmethod enabled the study of ET reactions in the late 1940s.13
In 1952, Mulliken developed a quantum mechanical theory thatdemonstrated that the donor-acceptor interactions stabilize theground states of the EDA complexes.14 The formation of acolorful solution was described as the diffusion-controlledformation of an encounter complex [D, A] followed by thespontaneous partial charge transfer or SET to generate thecolored species shown in Scheme 2.
In 1953, after Mulliken elaborated the theory of EDAcomplexes and of the SET in organic compounds, Taubedescribed the SET between two metal complexes and made thedistinction between “inner-sphere electron transfer” (ISET)and “outer-sphere electron transfer” (OSET).2a,b,16 Accordingto Taube’s original definition, ISET refers to SET between twometal centers containing a bridging ligand, while OSET refersto SET in the absence of a bridging ligand.In 1956, Marcus developed a theory to describe the reaction
rate of OSET calculated from the energy changes in theprocess.17 He conceived the SET for weakly interacting donor−acceptor complexes in a way similar to that of Mulliken(Scheme 3).
Experimental chemists including Sutin and Bennett meas-ured the rates of ET processes and compared them to valuespredicted by Marcus theory, which confirmed the accuracy ofthe Marcus equation in the early 1960s.17a In the early 1980s,Huber confirmed the Marcus theory and brought the SETprocess to the field of biochemistry through his work on thepurple bacteria photoreaction center.18 The Marcus theory canalso be understood from the schematic shown in Figure 1.Figure 1 shows the ET energy profile between two molecules
of the same species. Type S exhibits weak interaction betweenD and A, and the electron transfer has a high activation energy.Type M showed that the moderate interaction between D andA lowers the activation energy barrier. Last, type L is anextreme case in which a bond forms between D and A as can beseen from the energy minimum on the energy diagram.15
By the end of the 1970s, the distinction between OSET andISET was defined only on the basis of interactions of metalcenters. In the early 1980s, Eberson, Chanon, and Kochiadapted the ET theory to organic chemistry and expandedTaube’s original definition of ISET and OSET to organicdonors and acceptors (Scheme 4).15,19
The HDA in Scheme 4 refers to the donor−acceptorinteraction enthalpy. The OSET process as defined by Marcus,
Taube, Eberson, Kochi, and IUPAC refers to a SET processcharacterized by a transition state in which the donor andacceptor interact weakly (HDA < 1 kcal/mol), while ISET refersto a SET process wherein in the transition state the donor andacceptor interact strongly (HDA > 5 kcal/mol). However,considering the continuous change of HDA between OSET andISET, the commission of physical organic chemistry from theorganic division of the IUPAC defines the SET process withHDA values lower than 4 kcal/mol as OSET.20 Solvatedelectrons and radical anions are classic OSET donors.The polar mechanism contrasts the SET mechanism, because
it involves the transfer of one pair of electrons. A briefdiscussion of the polar mechanism is needed to clarify thisissue. Pross and Shaik noted the similarity of polar processesand two independent SET processes in the reaction-coordinatediagram.21 In short, the transfer of a pair of electrons can bestepwise, one electron at a time, and thus it could represent aSET process. This comparison is outlined in Scheme 5. The
classic SN2 reaction involving the displacement of iodide withan amine can be presented as a SET-induced C−I bondbreakage followed by the combination of the amine radicalcation with the methyl radical. Ashby proposed SETmechanisms to replace the conventional polar mechanisms inseveral reactions including the Grignard reaction and metalhydride reduction.22 However, some of the discussions of polarversus SET mechanisms in these reactions are controversial. Inthis Review, we will try to avoid this controversy, and,therefore, we will only discuss processes that were proven to
Scheme 2. Mulliken Definition of ET15
Scheme 3. Marcus Conception of OSET15
Figure 1. Potential-energy surfaces for self-exchange electron transfer(red) relative to the excited states (black) based on the two-stateMulliken−Hush formulation. Reprinted with permission from ref 15.Copyright 2008 American Chemical Society.
Scheme 4. OSET, ISET, and Polar Stepa
aValues defined by Eberson and Kochi.15,19 Values in parentheses weredefined by IUPAC to account for the continuous character betweenOSET and ISET.20 HDA is the donor-acceptor interaction enthalpy.
Scheme 5. Comparison of Polar Process with SET Process21
proceed via radical or radical ion mechanisms by sufficientexperimental evidence.The differences between OSET, ISET (Scheme 6), and polar
processes can also be understood from the potential energysurface diagram of the SET process (Figure 1).
It is noteworthy to mention that no distinguishable boundaryexists between ISET and OSET. Moreover, because theinteraction between D and A is largely dependent on theligand, nature of D and A, as well as the solvent used in thereaction, classifying one type of reaction being OSET or ISETis not always possible. To be more accurate in representing theSET donors and adducts, for even electron donors such asneutral organic compounds, radical anions or radical cations aregenerated after SET. However, for odd electron species, such asalkali metals and Cu, a cation or anion is generated after SET.This is outlined in Scheme 7.
Today SET is defined by the commission of physical organicchemistry from the organic division of the International Unionof Pure and Applied Chemistry, as “a reaction mechanismcharacterized by the transfer of a single electron between the
species occurring on the reaction coordinate of one of theelementary steps.”20
2.1.2. Dissociative and Sticky Single Electron Transfer.In the study of electrode-catalyzed DET to organic halides,Saveant observed a significant increase in SET rate to organichalides with electron-withdrawing groups such as perfluoroalkylhalides,23 carbon tetrahalides,24 and haloacetonitriles.25 Theinteraction of a radical with partial positive charge density andthe anion formed during the DET process in a solvent cage wasproposed to account for the acceleration of the SETprocess.25,26 This effect can also be represented in the energydiagram of the homolytic and heterolytic bond dissociationprocess (Figure 2).27 The blue line showed the energy profile ofthe homolytic cleavage pathway. The dashed and dotted redline showed the heterolytic cleavage of R−X in completelyrepulsive fashion without interaction between radical anddipole. The dashed black line represents the energy change ofheterolytic cleavage of R−X with strong interaction betweenthe radical and the anion. When the organohalides haveelectron-withdrawing groups attached, the radical will have apartial positive charge, which electrostatically interacts with thenegatively charged halide anion dissociated from organo-halides.27 This electrostatic interaction between partiallypositive charged radical carbon atom and the anion is called“stepwise sticky dissociation”.25 Although this interactiongenerates an intermediate, the SET process and the bondbreaking are still concerted. The effect was provenexperimentally. However, when theoretical calculations werecarried out according to the Marcus equation or in solutionphase ab initio models, they typically failed to find theminimum corresponding to the radical−anion pair due to thelimitation of solvation modeling in traditional quantummechanics packages.8
2.1.3. SET in Organic Reactions. The SET process is veryimportant in the bond breakage and bond formation of organicreactions. The reactivity pattern of radical ions formed via SETis well established.4f,28 The MOs of neutral molecules and SETadducts are shown in Figure 3. The bond order of SET adductis lower than that of the neutral molecule, and, therefore, theenergy of bond breakage is lower.The bond-breaking energy for radical anions and radical
cations is lower than that of the corresponding neutralmolecules. Hence, the activation energy of an inert bond via
Scheme 6. OSET and ISET Defined by Kochi15
Scheme 7. Most Accurate Displays of SET in OrganicChemistry
Figure 2. Energy diagram for the self-exchange of R−X/(R·X−) in (a) concerted dissociation and (b) stepwise sticky dissociation. Reprinted withpermission from ref 27. Copyright 2008 John Wiley & Sons.
SET mechanism is generally lower than in a polar mechanism,such as in the case of SET-promoted Cope cyclization (Figure4).28a
The reaction pattern of SET process is summarized inScheme 8.
The radicals and radical ions generated from the SETprocesses react in coupling, single electron transfer, atom orgroup transfer, addition, and elimination reactions (Scheme9).30
The atom-transfer (AT) reaction refers to the abstraction ofan atom or group (GT) from an organic molecule to produce anew radical located at the former site of the abstractedfunctionality. The direction of the reaction is determined by itsexothermic character and by the reactivity of the newly formedradical. The groups commonly abstracted are hydrogen atoms,halogen atoms, as well as groups such as SR and SeR.31 Thesereactivity patterns of radicals will be discussed in reactioncontext throughout this Review. However, according toKochi,32 in most cases the involvement of either AT or SET
process for the reaction of an alkyl radical and a metal complexis not known because the product formation and stoichiometryin both cases are indistinguishable. For instance, the conversionof an alkyl radical to alkyl halide by CuIICl2 may appear as anAT process33 because the net reaction involves transfer of a Cl·(Scheme 10, a). Nevertheless, the isotopic labeling studies
showed that, depending upon the reaction conditions, such assolvent, the reaction also has a component that goes via a SETprocess (Scheme 10, b).34
2.1.4. Dissociative and Associative SET Processes. Inthe studies of SET of Cu0 to alkyl halides, perfluoroalkylhalides, and aryl halides, the terms stepwise dissociativeelectron transfer (DET) as well as concerted DET arefrequently encountered in the literature (Scheme 11).8,23,35
This concept was explained in greater detail in a reviewpublished from our laboratory in 2009.8 To summarize, whileIUPAC,20 Taube,36 Marcus,17a Eberson,4e and Kochi15 classifyISET and OSET by the interaction between D and A, Saveantclassifies reactions by the concertedness of SET process andbond breakage. In Saveant’s nomenclature, if the bond breakageis concerted with the SET process (concerted ET), the SET iscalled ISET; when the SET and bond cleavage process isstepwise (stepwise DET), the SET is called OSET.35,37
However, examination of other reactions reveals that an ISETprocess can be concerted or stepwise and an OSET process canbe stepwise as well as concerted as depicted in Scheme 12.Nelson also pointed out that the definitions of ISET and OSET
Figure 4. Schematic potential energy surface for neutral and cationic1,5-hexadiene Cope rearrangement. Values are in kcal/mol. Reprintedwith permission from ref 29. Copyright 2007 American ChemicalSociety.
Scheme 8. Reactivity Patterns of SET Processes30
Scheme 9. Reactivity Pattern of Radicals30
Scheme 10. SET Mechanism for Reaction of Alkyl Radicalswith CuCl2
32
Scheme 11. Stepwise and Concerted Electron Transfer8,23,35
are different according to different laboratories, and this createsconfusion unless the exact definition and its origins areprovided.28b As Nelson discussed, Taube36 was the first todefine the difference between ISET and OSET by theinteraction between D and A, and Eberson4e and Kochi15
adopted this definition. McLendon elaborated this definitionand defined ISET as processes when changes in bond anglesand bond lengths in the reactant and product molecules occurduring ET.38 Shaik and Fawcett considered both ISET andOSET as a continuum.39 According to Nelson, Saveantconsidered ISET and OSET as separate processes that competein a reaction.28b Throughout the rest of this Review, unlessspecifically mentioned, the ISET or OSET term used will befollowing the classification of IUPAC, Taube, Marcus, Eberson,and Kochi.2.1.5. Historical Evolution of the Definition of Atom-
Transfer and Chain-Transfer Reactions. The atom-transferradical addition (ATRA) reaction is not defined by IUPAC.According to Curran,31,40 the origin of atom-transfer radicaladdition (ATRA) reaction can be traced back to Kharasch,Engelmann, and Mayo who reported in 1937 the anti-Markovnikov addition of HBr to unsymmetrical alkenes inthe presence of a radical initiator and called it “the peroxideeffect” (Scheme 13).41
In 1945, soon after the seminal publication of the anti-Markovnikov radical addition of HBr to alkenes,41 Kharaschand co-workers reported the addition reaction of CBr4, CCl4,CBr3Cl, and CCl3Br to olefins to generate polyhalogenated
alkanes in the presence of organic radical initiators such asAIBN (Scheme 14).42,43
Kharasch’s laboratory also reported that a variety ofsubstrates such as hydrocarbons, polyhalogenated alkanes,alcohols, ethers, amines, aldehydes, ketones, aliphatic acids,esters, and compounds of sulfur, phosphorus, silicon, tin, andgermanium can be used in the ATRA reactions.40b Curranreviewed the progress of ATRA reaction and summarized thegeneral reaction scheme and mechanism (Scheme 15).31,40
The abstraction of X atom by In· results in generation of theinitial radical Y· (step i, Scheme 15). Addition of Y· to alkene(step ii, Scheme 15) and further generation of Y· (step iii,Scheme 15) are the propagation steps. The key step in thisreaction is the abstraction of X· from X−Y, and the derivedradical (Y·) continues the kinetic process. X−Y is called thechain-transfer agent. Because in this reaction the Y· radical,which undergoes an addition reaction to the olefin, is generatedby an atom abstraction step (from X−Y), Curran coined theterm “atom-transfer addition” reaction to describe this process.Curran pointed out that for the ATRA reaction to competefavorably with the propagation reaction (i.e., step iii to be fasterthan step iv, Scheme 15), the ATRA reaction (steps ii and iii inScheme 15) must be rapid and exothermic. The addition step(step ii in Scheme 15) is exothermic by >20 kcal/mol due tothe formation of two strong σ-bonds at the expense of a π-bond.31 For a successful ATRA reaction to happen, the initialradical site (Y· in Scheme 15) must be more stable than the
Scheme 12. Stepwise DET Mechanism for Both OSET andISET Processes
Scheme 13. Radical Addition of HBr to Alkene41
Scheme 14. Preparation of Polyhalogenated Alkanes viaKharasch Addition Reaction42
Scheme 15. General Reaction and Mechanism Scheme ofATRA Reaction31,40a,b
adduct radical (YCH2CH·R in Scheme 15).40b The stability ofradicals was established from copolymerization experiments1,44
and is determined by steric, inductive, and resonance effects asoutlined in Scheme 16.
A major limitation of ATRA reaction is the formation of asignificant amount of oligomers and polymers from reactivealkenes such as Sty, methyl methacrylate or methyl acrylate(Scheme 17). Only unreactive olefins containing aliphaticsubstituents result in good selectivity for ATRA.
Radical cyclization additions (first-order rate of reaction) aremore efficient than linear additions (second-order rate ofreaction) in ATRA reactions. The decrease in entropy is smallerduring the intramolecular addition for the formation of five- orsix-membered rings than for linear addition. Also, for kineticreasons, the formation of the five-membered ring containing aprimary radical is faster than that of the six-membered ringcontaining a less reactive secondary radical (Scheme 18). The
kinetically controlled five-membered cyclic primary radicalundergoes faster hydrogen atom-transfer reaction than theradicals responsible for linear polymerization.40a,b,45 Thesynthetic aspects of cyclization reaction will be discussed inmore details in sections 3.2.3.1 and 3.5.2.In 1956, Minisci’s laboratory attempted the thermal
polymerization of acrylonitrile in CCl4 and in CHCl3 in asteel autoclave. Surprisingly, considerable amounts of mono-adducts, CCl3−CH2−CHClCN and CHCl2−CH2−CHClCN,resulting from the radical addition of CCl4 and CHCl3,respectively, to acrylonitrile were isolated.47 In 1961, Minisciproposed a redox mechanism involving FeCl2, obtained fromthe corrosion of the autoclave, to explain this radical additionreaction (Scheme 19).48 This reaction pioneered the field oftransition metal-catalyzed ATRA.
In 1963, Asscher and Vofsi reported the generation of 1:1adducts by CuI, CuII, FeII, and FeIII-catalyzed addition reactionof an olefin or conjugated diene and an organic polyhalide.49
The proposed mechanism for the chlorination reaction of theolefin by CCl4 was suggested to involve a redox transfer or aSET process by which the trichloromethyl radical wasgenerated to initiate a chain reaction (Scheme 20).49,50
In 1973, Asscher and Vofsi also reported the CuCl2-catalyzedaddition reaction of benzenesulfonyl chloride and CCl4 to anumber of styrenes carrying substituents of widely differentelectronegativity (Scheme 21).51 From the kinetic study of the
addition of benzenesulfonyl chloride to the substitutedstyrenes, they demonstrated that the effect of varioussubstituents on the overall rate of reaction was insignificant.This observation could not be explained by a concertedreaction, in which the styrenes should participate in the rate-determining step. Therefore, they confirmed the involvement ofa redox chain mechanism.51
The ATRA reaction has been further developed by thepioneering work of various research groups, such as the Gieselaboratory in the field of tin hydride-mediated radical additionto olefins,52 the Barton laboratory in the field of radicaldecarboxylation and deoxygenation,53 and the Curran labo-
Scheme 16. Stability of Radicals40c
Scheme 17. Oligomers and Polymers Formed via ATRAReaction41
Scheme 18. Cyclization Reaction via AT46
Scheme 19. Generation of Cl3C·48
Scheme 20. Mechanism of Copper-Catalyzed ATRAReaction Proposed by Asscher and Vofsi49
Scheme 21. Mechanism of Copper-Catalyzed ATRAReaction of Sty Proposed by Asscher and Vofsi51
ratory in the field of iodine atom-transfer radical reac-tion.31,40c,54 The application of various transition metalcomplexes in ATRA reaction showed better halogen atom-transfer reactivity than alkyl halides, which improved theselectivity of the addition reaction over oligomer and polymerformation.40b Transition metal complexes of Cu,45a Fe,55
Ru,45c,56 Ni,57 metal oxides,58 and zero-valent metals, such asCu0, Fe0, were used in the generation of free radicals.59
Inorganic and organometallic chemists define atom transferin a different way from organic chemists. Taube defined “atomtransfer” as “an atom originating in the oxidizing agent istransferred to the reducing agent so that in the activatedcomplex, both centers are bound to the atom beingtransferred.”60 Kochi investigated the radical formation processduring the reduction of organic halides by CrII and found thatthe generation of radicals (Scheme 22) showed no polar
effect.61 Kochi called the transfer of a halide atom between alkylhalide and CrII an atom-transfer process (Scheme 22).62 Thephysical organic/electrochemist Saveant also call this process(Scheme 22) atom transfer.63 Moreover, Saveant considersatom transfer formally equivalent to the ISET process.35
In contrast to the term atom transfer used in organic,inorganic, and organometallic chemistry, a similar term “chaintransfer” was used to describe abstraction of an atom by aradical in polymer chemistry prior to the popularization of the“atom transfer”. IUPAC in “glossary of terms used in physicalorganic chemistry” defines chain transfer as “the abstraction, bythe radical end of a growing chain-polymer, of an atom fromanother molecule. The growth of the polymer chain is therebyterminated but a new radical capable of chain propagation andpolymerization, is simultaneously created.”20 Hence, in a chain-transfer polymerization reaction, the activity of a growingpolymer chain is transferred to another molecule via a chain-transfer process (Scheme 23).
Chain transfer was first observed by Taylor and Jones64 in1930 when they demonstrated that ethylene is polymerized bythe ethyl radical generated during the thermal decomposition of(Et)2Hg and (Et)4Pb. Flory was the first to elaboratemechanistically the concept of chain transfer. He coined theterm “chain transfer” and in 1937 incorporated the concept ofchain transfer in the kinetic treatment of vinyl polymerization.65
A series of papers by Mayo laid the foundation for thedetermination of the rates of chain-transfer reactions.66−68
Mayo discussed the possible chain-transfer steps involved in theuncatalyzed polymerization of Sty (Scheme 24).66 In thisreaction, the first step involves the interaction of two Stymolecules to produce two radical initiators (Scheme 24, i).
After the formation of the initiating radical, the growth of eachradical takes place by successive addition of the Sty monomer.Both radicals are capable of reacting independently, and,therefore, three simultaneous chain-transfer reactions can takeplace.In steps iv and v from Scheme 24, if the resulting radical is
capable of generating a new radical by addition to themonomer, then a new chain is formed; hence the chain-transfer steps do not affect the overall rate of polymerization. Incontrast, in the disproportionation step iii (Scheme 24), twoactive centers terminate each other. However, in all of thesecases, the average molecular weight of the polymer is reducedas compared to the calculated molecular weight. Chain transfercan be either introduced deliberately into a polymerization byusing a chain-transfer agent or it may be an unavoidable side-reaction with various components of the polymerization such asthe solvent, monomer, polymer, and other reagents. Forexample, Cuthbertson, Gee, and Rideal69,70 demonstrated thatin the case of the polymerization of vinyl acetate in toluene, therate constant and degree of polymerization are reduced due to achain-transfer reaction from the growing polymer chain totoluene. Chain-transfer reactions occur in most forms ofaddition polymerization including radical polymerization, ring-opening polymerization, coordination polymerization, ring-opening metathesis polymerization, anionic addition polymer-ization, and cationic addition polymerization. As compared tothe chain-transfer polymerization reactions, which weredeveloped in 1930s, radical addition to the double bond ofsmall molecules to yield new C−C bonds was pursued startingwith 1945 soon after the notable discovery by Kharasch of theaddition reaction of CCl3Br to olefins, which is known as theKharasch reaction.42
2.1.5.1. Co-Mediated Catalytic Chain Transfer. A majoradvancement in the field of chain transfer is the Co-mediatedcatalytic chain-transfer reaction. In 1980, Enikolopyan’s
Scheme 22. Atom Transfer As Defined by Kochi61,62
Scheme 23. General Mechanism of Chain Transfer
Scheme 24. Chain-Transfer Reactions in UncatalyzedPolymerization of Styrene66
laboratory71 discovered that certain low-spin CoII complexes, inparticular CoII porphyrin complexes (Scheme 25, A), catalyzed
the chain transfer to monomer and determined the molecularweight in the radical polymerization of MMA. However, thesyntheses of porphyrins are costly and the Co-porphyrincomplexes are colored. Inspired by the similarity betweencobalt dimethylglyoxime and cobalt porphyrins, O’Driscoll andco-workers72 used cobalt dimethylglyoxime, also known ascobaloxime (Scheme 25, B), for the catalytic chain transfer infree radical polymerization of MMA. Cobaloximes are easy toprepare, less colored as compared to cobalt porphyrins, andexhibit good solubility and tunable reactivities (by axial ligands,L and equatorial ligands, R). The disadvantages of cabaloximecatalysts are their susceptibility toward hydrolysis andoxidation. O’Driscoll improved the stability of the cabaloximecatalyst to water and oxygen by the incorporation of BF2bridges in the third generation of CoII catalysts (Scheme 25,C).73
Excellent studies by Gridnev and Ittel,74 Solomon,75
Janowicz,76 Haddleton,77 and others generated insight intothe mechanism of the catalytic chain-transfer process. The mostaccepted mechanism involves the abstraction of a H atom fromthe propagating chain end and the formation of a cobalt-hydride intermediate as shown in Scheme 26.
In Co-CCT, one polymer chain end typically results in anactivated olefin, for example, with monomers containing an α-methyl group, such as MMA, a H atom abstraction taking placefrom the α-methyl group, whereas for monomers without an α-methyl group, such as Sty, H abstraction takes place from thebackbone.79 Considering that the CCT step forms most of thepolymer chain end in the reaction, these polymers are furtherused as macromonomers in polymer synthesis. For example,
highly structured pigment dispersants containing both hydro-phobic and hydrophilic groups for paints80 and branched blockor graft copolymers can be prepared from these macro-monomers.19,81
2.1.5.2. CoII-Mediated Living Radical Polymerization. In1994, cobalt-mediated living radical polymerization of acrylateswas reported.82 Wayland and Fryd82 reported the LRP of MAwith Co-porphyrin complexes with linear kinetics up to Mn =170 000 and Mw/Mn = 1.1−1.3. The metalloradical eliminatedthe biradical termination by the persistent radical effect.82 Blockcopolymers of MA with butyl acrylate were prepared using thiscatalytic system.83 In the meantime, the Harwood laboratoryreported the photoinitiated LRP using alkyl cobaloximes.84
Acrylate monomers including ethyl acrylate were accessed bythis LRP methodology.84 The Co-catalyzed LRP was limited toacrylic esters and acids until the discovery of Co(acac)2-catalyzed LRP of vinyl acetate reported in 2005.85 This LRPshowed linear kinetics despite an induction period of 12 h at 30°C. Polymerization initiated with a macroinitiator wasconducted, and the resumption of the VAc polymerizationwas observed. In 2008, the LRP of acrylonitrile by usingCo(acac)2 was reported with Mw/Mn as low as 1.1 at 0 °C inDMSO.86 Wayland and Fryd demonstrated that other organo-cobalt complexes mediate the LRP.87
Several other living radical polymerizations such as RAFT,SET-DTLRP, and iodine transfer polymerization incorporatethe concept of chain transfer.88,89 In these processes, the chain-transfer reaction produces a polymer chain with a chain-transferactivity similar to that of the original chain-transfer agent.Hence, there is no net loss of radicals during the chain-transferactivity.
2.1.6. Comparison between Chain Transfer and AtomTransfer. The name atom transfer is primarily used in organicreactions, most notably in the ATRA cyclization reaction, whichis discussed in sections 2.1.5, 3.2.3.1, and 3.5.2. The comparisonbetween ATRA and CT is discussed in Scheme 27. Accordingto Curran,40a in the initiation steps (steps i and ii, Scheme 27),the unreactive initiator radical of the ATRA (Cl3C·) isgenerated by a kinetically controlled process due to thepresence of CCl4 in large excess. In the propagating step, theunreactive radical Cl3C· adds to an unactivated olefin,generating the more reactive propagating radical(Cl3CCH2(n-hexyl)CH, step iii, Scheme 27). This reactivepropagating radical (Cl3CCH2(n-hexyl)CH, step iv, Scheme27) rapidly abstracts a Cl· from CCl4 (the chain-transfer stepthat in this case is named AT) and regenerates the more stableinitiator radical (Cl3C·, step iv, Scheme 27). In ARTA, the atomdonor (CCl4, Scheme 27) should be able to undergo chain-transfer reactions or AT, much faster than the propagation ortermination. A higher rate of propagation over AT requires anactivated olefin and results in oligomerization and polymer-ization (vii, Scheme 27).40a On the other hand, chain transfer isthe fundamental step from a polymerization reaction by whichan atom is abstracted by a growing propagating radical togenerate a new radical, which must be capable of further chainpropagation and polymerization via an addition reaction to themonomer. There are several types of chain-transfer reactions,including chain transfer to polymer, to monomer, to solvent, orto a chain-transfer agent (steps viii and ix, Scheme 27).20
Usually, chain-transfer agents carry a weak chemical bond,which facilitates the chain-transfer reaction. For many industrialprocesses, a chain-transfer agent is added to the polymerizationto obtain a well-defined polymer molecular weight.90
Scheme 25. Structures of CoII Catalysts for Catalytic ChainTransfer
Scheme 26. Main Catalytic Cycle for Cobalt-MediatedCatalytic Chain Transfer74a,78
Commonly used chain-transfer agents in free radical polymer-izations include thiols, such as dodecyl mercaptan, andhalocarbons such as CCl4 and others.
2.2. Classes of Electron Donors and Acceptors
2.2.1. Inorganic Electron Donors and Acceptors. Zero-valence metals serve as inorganic electron donors. Metalcomplexes can be electron donors or acceptors depending onthe oxidative state of metal centers. Moreover, the dispro-portionation of metals should be considered in all reactions. Abrief discussion of copper species is included due to theimportance of copper in SET reactions.2.2.1.1. Metals as Electron Donors. Metals are ubiquitous in
nature. Metals are intrinsically electron donors because theytend to form cations through loss of electrons. Multiple metalscan serve as electron sources for reduction of organiccompounds, generating radical anions and radicals (Scheme28). The main group metals were first applied as SET donors inorganic chemistry two centuries ago.11
Alkali metals, including Li, Na, K, find use in the reduction ofalkyl halides such as in the Barbier reaction91 and Wurtzcoupling,10 in generating solvated electrons such as in the Birchreaction,92 in preparation of aromatic hydrocarbon radicalanions,93 in cyclization reactions mediated by solvatedelectrons,94 and in reduction of sulfones as in the Julia−Lythgoe olefination.95 The alkali earth metals, Mg, Ca, Sr, arealso SET donors. For example, Mg is well-known to organicchemists for Grignard reagents formation.96 Calcium was usedin SET-induced epoxide ring-opening.97 Sr is also used in theBarbier reaction.91 Aluminum is a common electron source.98
In is also capable of various SET reactions including radical
addition and ring expansion reactions.99 The similarity of group16 elements Se and Te with S led to the study of SRN1 reactionmediated by both Se and Te.100 Transition metals also foundtheir use in SET reactions. Transition metals typically havemultiple oxidation states, leading to diverse chemistry includingSET processes. The transition metal complexes acting aselectron donors and acceptors will be discussed later. The useof transition metal0 in organic chemistry is well documented.Cu0 is a classic SET donor used in the Ullmann reaction,101 thePschorr reaction,102 the reductive dehalogenation of alkylhalides,103 in the Muller−Rochow process,104 as well as in SET-DTLRP and in SET-LRP.8,105 All 3d metals were found reactivein the reductive dehalogenation of alkyl halides through SETmechanism.106
2.2.1.2. Metal Complexes as Electron Donors andAcceptors. The existence of multiple oxidation states of metalsenables their complexes to function as both electron donors
Scheme 27. Comparison between Atom-Transfer Mechanism Proposed by Kharasch42 and Chain-Transfer Reactions Proposedby Mayo66
Scheme 28. Zero-Valence Metals as SET Donors in OrganicChemistry
and acceptors. Nature uses a number of metals in key redoxsystems such as in photosynthesis.107 It is impossible to list allmetal complexes used as SET donors and acceptors in organicand polymer syntheses. Therefore, only a brief discussion isprovided here. High-valence metal complexes (MnL) are goodelectron acceptors. When the one-electron reductant of MnL(Mn−1L) is accessible, the complex is a potential SET acceptor.High-valence transition metal complexes commonly used asSET acceptors include: CeIV, MnV,108 TiVI,109 CuII, FeIII, NiIII,AgI, as well as RhIII.110 Transition metal hexahalides such asMoF6, WF6, and UF6 were also recommended as one-electronoxidants.110 Low-valence metal complexes can serve as SETdonors, such as MnIII, FeII, CuI, RhII, NiI, low-valence Ti, andlanthanides complexes such as SmI2.
111 Zero-valence metalcarbonyl complexes are also good donors and were used toinitiate radical polymerization reactions by the SET process.112
2.2.1.3. Disproportionation of Metal-Containing Com-pounds. The process in which species of the same oxidationstate combine to generate species of higher oxidation state andwith lower oxidation state is called disproportionation [(x +y)Mn → xMn−y + yMn+x; M is the atom that disproportionates;n, n − y, and n + x are the oxidation states of the atom].20,113
Common metal ions that disproportionate in aqueous solutioninclude Cu+,113,114 Cd2
2+, Mn6+, Hg22+, Sn2+, Ga+, In+, Au+, and
Sm2+.115 Ag+ is usually stable in water. The equilibriumconstant for the disproportionation (Kdisp, Table 1) of Ag+
(2Ag+ → Ag0 + Ag2+) is 10−20.116 However, in the presence ofstrong basic ligands such as tetrazaamacrocycles, thedisproportionation of Ag+ occurs.116,117 The extent ofdisproportionation of metal ions in aqueous solution can becalculated from electrochemical data. However, it is importantto take the ligand, the solvents, and the anion intoconsideration.118 Cu+ will be used as an example. Theequilibrium constant of the reaction 2Cu+ → Cu0 + Cu2+
without the addition of an external ligand in water reported inthe literature ranges from 106 to 107.114,119 However, the Kdispin MeCN for the same disproportionation is only 10−21 (Table1).120 As far as the effect of ligand on Kdisp, Percec’slaboratory118 demonstrated that the extent of disproportiona-tion is dependent on the stabilization effect of ligand to Cu2+.Cu2+ stabilizing ligands such as Me6-TREN, TREN, and PEIincrease Kdisp significantly (Table 1).118,121
The amount of the ligand also impacts the Kdisp.118 The
stabilization effect of amine-based ligand on CuI and CuII
species was evaluated by DFT methods.133 The disproportio-nation process was studied both by spectroscopic methods andby direct visualization.118,134 The Cu0 species generated fromdisproportionation exist in colloidal state when the solvents
stabilize the Cu0 atomic species, such as DMSO, DMF, DMAc,and NMP. The “nascent” Cu0 atoms and naoparticles generatedin situ showed higher reactivity in reaction as compared to bulkCu0 powder considering the size-dependent reactivity discussedhereinafter. In solvents that do not stabilize Cu0, includingwater, acetone, EC, PC, and alcohol, the Cu0 atoms nucleate,aggregate, and precipitate into nanoparticles of different size.118
Therefore, disproportiation must be considered in themechanism of organic and polymerization reactions, whendisproportionating metal species are used as reagents.
2.2.1.4. A Brief Discussion of Copper Species. Because ofthe importance of copper catalysts in organic as well as polymerchemistry, several forms of copper salts will be discussed briefly.The common CuCl, CuBr, CuCl2, and CuBr2 exist in crystallinesolid forms. Skillful methods were applied to isolate CuF-(PPh3)32ROH and then evaporate the volatile ligand andsolvent to prepare CuF in gaseous phase. However, the attemptto condense the CuF from gas phase to solid form failed.135
Theoretical work led to the conclusion that CuF might exist ingaseous phase, but attempts to isolate solid CuF led to thedisproportionation of CuF to Cu0 and CuF2.
136 CuI2 does notexist in aqueous solution either, because I− is a good electrondonor and readily reduces CuII to CuI to generate the waterinsoluble CuI.137 However, in the presence of CuII stabilizingligand such as TREN, the CuI2(TREN) obtained fromdisproportion of Cu+ in the presence of TREN and I− wasshown to be persistent in single electron transfer degenerativechain-transfer living radical polymerization (SET-DTLRP) ofVC and in SET-LRP of acrylates.137
It is difficult to discuss the reductive potential of Cu specieswithout mentioning the reaction solvent, ligand, concentration,and counteranions. The lower standard oxidation potentialagainst standard hydrogen electrode of Cu0 than CuI inaqueous solution at standard conditions (salts in 1 Mconcentration, temperature 25 °C, metal in pure form, andgas at 1 atm) shows that, without considering the contributionsof ligand(s) and counteranion(s), Cu0 is more prone tooxidation than CuI under standard conditions (Scheme 29).115c
2.2.2. Organic Electron Donors and Acceptors. Inorganic synthesis by SET processes, the commonly usedelectron donors are metals, metal complexes, or organometalliccompounds. However, neutral organic compounds can act as
Table 1. Equilibrium Constants for the Disproportionation of CuIX, in Various Solvents in the Absence (Kdisp) and in thePresence (K*disp) of a Liganda118
IX]2); K*disp = ([Cu0][CuIIX2/L][L])/([CuIX/L]2). bKdisp observed at the most effective concentration of ligand for
disproportionation in that solvent. CuIBr was used. cThe constant at the most effective concentration of ligand is not determined because theabsorbance indicates greater than 100% disproportionation.
Scheme 29. Standard Oxidation Potential of Cu0 and Cu+115c
electron donors, having a suitable oxidation potential inspontaneous reactions, or by other stimulating conditions,such as thermal, photochemical, electrochemically, or byradiolysis. The electron donor properties of aromatic aminesby spontaneous reaction with a suitable acceptor have beenknown since the 1800s when the discovery of Wurster’s Redand Blue salts was reported.138 Dithiadiazafulvalenes, polyaza-substituted ethenes, along with their parent compoundtetrathiafulvalene139−141 are other classes of reagents thatshow electron-donating ability by spontaneous or photo-chemical processes. Several tetraazafulvalene derivativessynthesized by Murphy laboratory are shown to have verystrong electron-donating properties, and, therefore, they arecalled “super organic donors”.141 In addition, amines inprimary, secondary, or tertiary form act as electron donors inthermal or photochemical reactions via formation of aminiumradical cations.142−145 In the presence of strong oxidants, suchas ceric ammonium nitrate (CAN), FeIII salts, MnIII salts,hypervalent iodine reagents, and others, many organic reagents,such as enamine, olefins, enolates, phenolates, aromatic, andheteroaromatic compounds, act as efficient electron donors andare frequently used in organic synthesis.140
On the other hand, many organic reagents, alkyl halides, arylhalides, aryl azide, olefins, ketones, perfluoroalkyl halides,sulfonyl halides, N-halidesuccinimides, 5-halogenouracils, disul-fides, bromonitrile, aromatic, and heteroaromatic compounds,show efficient SET acceptor properties by spontaneous,thermal, electrochemical, or radiolytic processes in the presenceof organic or inorganic electron donors. In numerous cases, theradical anions generated via SET to these acceptors wereidentified and analyzed by ESR techniques (section 2.3.2.1).The electron-accepting properties of alkyl halides have beenknown since 1855 from the Wurtz reaction, which results in thecoupling of two alkyl halides by a SET process from sodiummetal.10,146 Followed by the electron transfer to the alkyl or arylhalide bond, cleavage is one of the most common modes ofreaction by which a free radical and a diamagnetic leaving groupare produced. The cleavage of the σ-bond may follow either aconcerted or a stepwise mechanism. In the case of ketones andolefins, the formation of distonic radical anions is the mostcommon outcome of the SET reaction. This is followed byvarious types of rearrangements and cyclizations, which resultin many important organic reactions. Early organic andpolymerization reactions involving SET to alkyl halides areBarbier, Grignard, Wurtz, Kagan−Molander, Ni-catalyzedcross-coupling reactions, and various living radical polymer-izations. Epoxide ring-opening, Birch reduction, Meerweinarylation, Sandmeyer reactions, Ullmann reactions, Gomberg−Bachmann−Hey reaction, Pschorr cyclization from aryl halidesor aryl azides, and living anionic polymerization of Sty initiatedby electron transfer from the outer-sphere electron donornaphthalene radical anion and related compounds are alsoimportant reactions involving SET to organic acceptors.2.2.3. Electrochemical. In organic electrosynthesis, the
conversion of a reactant to the desired product is based on twofundamental SET steps, anodic oxidation or cathodic reduction.In anodic oxidation, the anode acts as the electron acceptor andthe HOMO of the reacting substrate as the donor. On theother hand, in an organic reaction involving cathodic reductionstep, the electron donor is the cathode and the LUMO of thereacting substrate is the acceptor. Any material that allows forthe transfer of electrons in solution and are stable in thereaction condition can be utilized as electrodes. Some
commonly used materials as anodes or cathodes in organicelectrosynthesis include platinum (wire, mesh, or foil), carbonrods, carbon plates, magnesium, stainless steel, or reticulatedvitreous carbon (RVC) or glassy carbon. Various electrodes,such as glassy carbon, act as OSET donors due to their inertnature. Hg, Cu, Ag, Pd, Pt electrodes may get involved in theformation of transition state and therefore are considered to actas ISET donors and even have catalytic properties such as inthe case of copper.147 In addition to the choice of solvent,electrolyte, current density, and continuous or selective modeof electrolysis, the material of the electrodes also needs to beoptimized because that can affect the reaction outcomeextensively. One of the major differences between organicelectrosynthesis and common organic chemistry is that in theformer case the activated species is not generated uniformly inhomogeneous solution by reacting with donors (cathode) oracceptors (anode), but only on the surface of electrodes.Hence, the effective concentration of the resulting radical anionor radical cation is significantly higher during the reaction,which results in lower selectivity of the reaction. By contrast, incommon organic reactions, the active species generated fromelectron donors or electron acceptors are uniformly distributedin solution and result in product formation with higherselectivity. On the other hand, an important advantage oforganic electrosynthesis over common organic reactions is thatin the later case the inversion of polarity (umpolung) of themain reacting species (donors or acceptors) is achieved simplyby electrolysis, which is not feasible in the former case wherenormally SET takes place between a nucleophile and anelectrophile.
2.3. Classes of SET Adducts
2.3.1. Radicals. In organic and polymer chemistry, reactionsinvolving free radicals as intermediates or in some cases withpersistent radicals are frequently encountered events in additionto formation of anions, cations, radical ions, and charge-transfercomplexes as intermediates. Carbon-centered radicals havebeen known for almost two centuries.4i Gay-Lussac reportedthe formation of cyanogen (dimer of NC·) by heating mercuriccyanide in 1815.148 The electrosynthesis of dimeric alkanesfrom carboxylates by anodic oxidation demonstrated byFaraday in 1834 was one of the early examples of radicalformation by electrolytic oxidation.149 Moses Gomberg firstproposed the concept of radicals in 1900 when hedemonstrated the existence of a trivalent carbon, triphenyl-methyl radical.150 Although this discovery was followed bysome studies in the gas-phase radical processes during the nextthree decades, the application of radical chemistry in organicsynthesis in solution was pioneered mostly by Waters, Hey,Kharasch, and Mayo. The historical development of carbon-centered radicals was highlighted by Forbes.4i Their studiescommenced the development of organic free radical chem-istry.151−154 In a chemical reaction, radical intermediates can begenerated by two types of SET processes: one-electronoxidation of an anion or reduction of a cation (Scheme30,a,b), and a SET process followed by homolytic σ-bondcleavage by a stepwise or concerted pathway (Scheme 30,c).The radical formation by both types of processes will be
observed and discussed throughout this Review in variousreactions. SET reactions from a nucleophile in the SRN1reaction, reduction of aryldiazonium cation by SET from a CuI
catalyst, are examples of the first type of reaction. Irradiation oftriphenylmethyl (trityl) anion in DMSO gives rise to efficient
SET reaction to DMSO to generate DMSO radical anion andtrityl radical, which eventually produce 1,1,1-triphenylethaneand p-tolyldiphenylmethane as primary products (Scheme 30,a).155 Synthesis of poly(phenyl ether)s (PPE) by SET oxidationof phenolate resulting in phenol radical occurs due to SET tothe phenolate via a SRN1 mechanism (Scheme 30, a).156 On theother hand, CuI-catalyzed SET of aryldiazonium cation inMeerwein arylation157 and Sandmeyer reactions158,159 areexamples of formation of radical intermediates by SETmechanism. Formation of radicals by SET involves the σ-bond cleavage of the radical anion produced by one-electronreduction of alkyl halides and aryl halides.A radical intermediate can react in three different ways: (i)
redox reaction or SET (Scheme 31, a), (ii) atom or grouptransfer (Scheme 31, b), and (iii) atom-transfer additionreaction (Scheme 31, c).
SET reactions involving radicals occur chemically orelectrochemically, and the rate of the SET step is determinedby the difference of the reduction potential between the radicaland the reductant (or oxidant). Normally, under conditions ofchemical and anodic oxidation, neutral radicals are, however,efficiently oxidized to cationic intermediates,160 such as α-amino radicals.161 In contrast to neutral molecules, radicals are
much easier to oxidize. Similarly, radicals with low-lying SOMOare reduced easily, like in the case of the malonyl radical.162
2.3.2. Radical Anions. Formation of an aromatic radicalanion was first recorded in 1867 when Berthelot described theappearance of a black addition product when fusing metallicpotassium with naphthalene. Initially it was considered that themetal was bonded to the aromatic ring.163 In 1936, Scott,Walker, and Hansley reported that the adduct was ionic ratherthan electrically neutral.164−166 Huckel and Bretschneider firstsuggested the idea that the adduct was formed via electrontransfer.93,167−169 In principle, any organic molecule hasantibonding molecular orbitals (MOs), so that essentially anyorganic molecule is capable of forming a corresponding radicalanion. However, the addition of an extra electron to a π-bond ismuch easier than to a σ-bond.28a The formation of a radicalanion can be achieved by one-electron reduction of any neutralsubstrate by chemical or electrochemical electron transfer,radiolysis, or photolysis. In the chemical methods, radicalanions have been generated by the reaction of an appropriateneutral molecule with metals in their zero-valent, higheroxidation states, and in some cases by organic electron donors,such as amines. One of the most noteworthy examples togenerate radical anions by metals as electron donors is theliving anionic polymerization reaction reported by Szwarc in1956.170 In this reaction, alkali metals are used to generate theradical anion naphthalene intermediate by an outer-sphere SETprocess to the acceptor having large electron affinity, such asaromatic (naphthalene), and subsequently by another outer-sphere SET to the unsaturated (Sty) molecules (Scheme 32).Radical anions and solvated electrons are classic outer-sphereelectron donors.
In this Review, SET reactions to various electron acceptororganic substrates, such as alkyl halides, carbonyl, olefins,epoxides, sulfones and other sulfur-containing compounds,arenes, aryl halides, and other conjugated systems will be shownto generate radical anion intermediates. Typical reactions ofradical anions include proton transfer, ET, and bond cleavage ofthe σ- or π-bond. Radical anions undergo SET reactions with avariety of acceptors, such as alkanes, olefins, alkyl and arylhalides, ketones, etc. The reducing property of naphthaleneradical anion is as high as that of metallic sodium. In the case ofaromatic halides (ArX, Scheme 33), SET takes place to the low-lying π* orbitals. This is followed by an intramolecular SETfrom the primary formed π* to the σ* (C−X), which isfollowed by cleavage of the latter (intramolecular DET). Thus,
Scheme 30. Generation of Radicals by SET
Scheme 31. Common Reactions of Radicals
Scheme 32. Radical Anion Intermediate in Living AnionicPolymerization of Styrene170
Scheme 33. Reductive Dehalogenation of Aryl Halides172
depending on the chemical structure of ArX, the energy of theσ* orbital varies.171 As a result, the ArX radical anions can havea large range of lifetimes. For example, the bond cleavage ratefor phenyl halide (k = 10−10 s−1) is 2 orders of magnitudehigher than that of nitrophenyl halides (k = 10−12 s−1) as aresult of the favored SET from π* to the σ* in the latter case.Usually π* belongs to an aromatic, heteroaromatic, vinylic, orheterovinylic (e.g., acyl group), and the σ* acceptor of C−halogen, C−O, C−S, C−Se, O−O, Si−halogen frequentlyundergoes fragmentation after formation of a radical anion.172
In the case of SET to alkyl halides, the mechanism ofgeneration of a radical anion as a distinct species and a stepwiseC−X bond cleavage continues to be debated (Scheme 34). In
many cases, a concerted SET process has been proposedwherein C−X bond cleavage takes place simultaneously withthe SET step (Scheme 34). However, the stability of thesetransient species depends on the environment, especially thetemperature and the solvent. Attractive interactions betweenion radicals and their environment may lower the energy of thecorresponding σ* populated with an unpaired electron.173 Thisenhances the stability of the radical anions and favors thestepwise pathway of the reaction. The competition betweenthese two reaction pathways depends upon both the drivingforces and the intrinsic barrier factors. If the concerted pathwayhas a stronger driving force than that of the first step of thestepwise pathway, the cleavage of the radical anion isthermodynamically favorable. Stepwise mechanisms are favoredwhen the intermediate has a lifetime longer than the time for abond vibration (ca. 10−13 s). However, according to Saveant,the concerted character of the reaction results from anenergetic advantage rather than from the “nonexistence” ofthe radical ion intermediate.174
In a study by M. Symons175 on the lifetime of alkyl halideradical anions, it was demonstrated that in the reaction betweenalkyl halides (R−X, Scheme 35) and disodium tetraphenyl-ethanediide (TPE2−), the halogen atoms play an active role.The product distribution is from two types of reactions, onethrough alkylation of aromatic ring from R• generated and onethrough further SET of R• to give R ion. A significant
dependence of the product distribution on halide ion (X),such as iodide giving reduction as the main product,demonstrated that in this reaction TPE2− gives the most stableR−I• radical anion. To explain this observation, Simonsproposed that R−X−· might have a finite lifetime.175
In electrochemical methods radical anions are generated bypotential-controlled electrolysis, and experiments are typicallyconducted in a special ampule placed into a resonator of theESR spectrometer that permits the detection of many unstableradical anions. In addition to the reductive SET processes,generation of radical anions has also been reported by couplingof a radical and an anion, and was detected by ESRspectroscopy. For example, the disulfur radical anion (RS−SR·) can be generated by a SET process to RS−SR moleculeand by an electron loss from RS-ions (Scheme 36).176
2.3.2.1. Radical Anion Intermediates Captured by ESR andOther Methods. As stated by Marcus,13 the innovation inexperimental techniques greatly promoted the advancement ofET theories. Great developments have been achieved in thefield of fast reactions. Ever since Porter and Norrish receivedthe Nobel Prize in Chemistry in 1967 for flash photolysistechnique (10−6 s resolution back then),177 observations oftransitions in femtosecond (10−15 s) time scale were achievedby Zewail and other researchers.178 Recently, the developmenton femtosecond spectroscopy enabled the observation oftransition states.179 The methods and techniques to study ETprocesses have been discussed extensively in previouslypublished book chapters and reviews.4b,j A brief discussionwill be provided here. Currently, the techniques can be devidedby the initiation of ET process to thermal, photochemical, andelectrochemical techniques.4j The differences between eachtechnique include the limitation of analysis time windows.4j Forexample, the observation of C−X bond dissociation of a seriesof aryl halide radical anions in NMP at room temperature bypulse radiolysis with 10−11 s resolution showed the dissociationwas 10−100 times faster as compared to the rates determinedpreviously by electrochemical methods.180 The kd determinedfor 1-iodonaphthalene in NMP is 5 × 1010 s−1 by pulseradiolysis and 2 × 109 s−1 determined by electrochemicalmethods.180 The development of pulse radiolysis in 2007 hasenabled the observation of transient adsorption of chemicalreactions in subpicosecond (10−14 −10−13 s) resolution, in thetime scale of bond vibration.181 This development might lead tothe discovery of new transient species during ET processes.Another important difference to notice is the method to initiatethe ET.4j While thermal homogeneous electron transfermethods, such as stop flow and continuous flow technique,involve the transfer of a single electron in homogeneousmedium, electrochemical methods, such as linear and cyclicvoltammetry, generally transfer multiple electrons in aheterogeneous fashion on the electrodes.4j In contrast,photochemical techniques, such as photolysis, involve reactantsin excited states. These different methods of initiation of ETmight lead to different reaction pathways afterward.4j Thus, the
Scheme 34. Reductive Dehalogenation of Alkyl Halides174
Scheme 35. Major Reactions between Alkyl Halides andTPE2−a
aThe large brackets indicate solvent cages.175
Scheme 36. Generation of Disulfur Radical Anion176
analysis time window and the methods of initiation of ETshould both be considered when judging data obtained fromdifferent experimental techniques.The ESR method observes unpaired electrons in the radical
anions and permits their analysis in a solid solution at lowtemperature such as 77 K, which avoids their cleavage intoradicals and anions. A list containing examples of radical anionsobserved and analyzed by ESR and other methods is providedin Table 2. The lifetime of radical anions is dependent on thestructure of the radical anion and medium.182 Some radicalanions are persistent due to stabilization by resonance, such asin the case of naphthalene170 and benzophenone radical
anions,183 while others show a short lifetime. For instance,the lifetime of CH3Cl
−· is as short as 3 × 10−8 s.184 The list inTable 2 is not a comprehensive list of radical anions that existfor finite lifetimes, but a list of radical anions identified by ESRand other methods.
2.3.3. Radical Cations. Radical cations are usuallygenerated by single electron oxidation of a neutral substrate.The commonly used oxidation pathways to generate radicalcations are chemical, electrochemical, and photoinduced. Inchemical oxidation processes, a spontaneous SET step takesplace from the HOMO of the molecule to an electron acceptorwith a suitable reduction potential. For example, in MacMillan’s
Table 2. Radical Anions Identified by ESR and Other Methods
SOMO catalysis, the reaction of an enamine with CAN at roomtemperature results in an aminium radical cation.202 Reactionsof various organic functional groups with metal salts, such asoxidation of trifluoroacetic acid with CoIII, have been identifiedvia ESR spectra of the resulting radical cations.203 The head-to-head cyclodimerization reaction in the presence of a variety ofSET donors, including FeIII, CeIV, CuII salts, occurs by theformation of radical cation intermediates. Application of stableaminium radical cations in [2 + 2] cycloaddition reactions ofelectron-rich olefins, such as styrenes, dienes, vinyl ethers, hasbeen known since the 1980s.160
In electrochemical methods, radical cations are generatedfrom heterogeneous anodic oxidation processes. Because in thismethod the radical cations generated on the surface of theelectrode have a very high concentration, their reactivity isusually less selective than the chemically generated radicalcations. However, a great advancement in this field has beenmade by the application of electrochemical mediators bySteckhan that function in homogeneous solution and thusprovide reaction conditions similar to those of commonchemical reactions.204 Photochemical SET to generate a radicalcation is a rather novel method that is an extensively usedoxidation method in organic synthesis. The formation of radicalcations by photolysis can take place by two different methodsby direct irradiation of donors or acceptors, and by using aphotosensitizer.205 Noteworthy examples of photoinducedradical cations formation include photolysis of amines, whichact as stronger electron donors than the ground-state form andgenerate an aminium radical cation. Hence, amines underphotolytic conditions can be used for many important organictransformations, such as intramolecular addition of the ketylradicals of α,β-unsaturated ketones, and cyclization of Br- or Cl-olefins by reductive dehalogenation reaction via one-electronreduction of the substrate. Many inorganic one-electronoxidants, such as Ru(bpy)3
2+ and its derivatives, underphotolysis have been used extensively for [2 + 2] cycloadditionreaction of electron-rich olefins.205
However, there are some nonoxidative methods that can alsogenerate radical cations, such as the Hofmann−Loffler−Fretygreaction, proton abstraction by a radical, pseudo (halogen)atom abstraction by a cation, heterolytic σ-bond cleavage of aradical, and homolytic σ-bond cleavage of a cation.205
2.3.4. Organometallic Adducts. The electron adductsformed during the reduction of alkyl halides with metal0 areorganometallic species (Scheme 37).Organolithium and Grignard reagents are commercially
available and widely used in synthesis.91,206 Organosodiumhalides are also generated via a SET process that is lessfrequently utilized in synthesis.146 The over-reduction of alkylhalides by SmI2 generates organosamarium species.207 In thecase of Cu, the formation of organocopper species in solution
was proposed when reacting benzyl halides with Cu0 onCu(111) surface at −98 °C (Scheme 38).208 The formation of
perfluoroalkyl copper reagent was proposed to proceed by SETto form the radical anion of the perfluoroalkyl iodide.Subsequently, the perfluoroalkyl radical is reduced on thecopper surface and generates the perfluoroalkyl copperreagent.209 Another proposed pathway for the formation oforganocopper reagents is the oxidative addition of ArXfollowed by subsequent reduction of ArCuIIXL with Cu0 togenerate ArCuIL species (Scheme 38). A third method is thetransmetalation of CuIX with organolithium, or with a Grignardreagent (Scheme 38).210 The last method does not involve SETprocesses.Simple aryl copper (Ar−Cu) species without the stabilization
of ligand decompose at 0 °C. Methyl copper in the dry statedecomposes with explosion at above −15 °C.210 According to asurface chemistry study, aryl copper species decomposes at 25°C (2RCu → 2R· + 2Cu → R−R + 2Cu).211 The stability oforganocopper species can be increased by the addition ofexternal ligands as well as by intramolecular binding.210 So far,the majority of organometallic Cu adducts are CuI species.Only a few examples of organo CuII species were reported.210
This might come from the oxidative tendency of CuII that leadsto the decomposition of R2Cu
II species to R·. The facilereductive elimination of R2Cu
II to R−R and Cu0 is alsoproposed to account for the instability of R2Cu.
210 Surprisingly,even though organocopper species are not stable, organo-copperIII such as Br2Cu
IIIS2CNEt2 was isolated and charac-terized by X-ray crystallography.210 The generation of organo-nickel complex via SET processes was proposed by Kochi toexplain the homocoupling catalyzed by Ni.212 However,Klabunde reported that the organonickel species generatedfrom reacting nickel vapors with alkyl halides without additionof ligands are not stable.213
3. REDUCTIVE CHEMISTRY
3.1. SET Reactions with Alkyl Halides
3.1.1. The Barbier Reaction. In 1899, Victor Grignard’steacher Philippe Barbier reported the synthesis of secondaryalcohols by reacting an alkyl iodide with an aldehyde in thepresence of Mg (Scheme 39).214
Scheme 37. Generation of Organometallic Adducts via SETwith Alkyl Halides
Scheme 38. Formation and Cleavage of OrganocopperReagents210
This reaction at first glance might appear to be a Grignardreaction carried out in situ that may avoid the isolation of theunstable Grignard reagents.215 The fact that the Barbierreaction has high tolerance to water indicated that a closerinvestigation of the mechanism was needed. The reactionmechanism was proposed to proceed via two steps (Scheme40). The mechanisms of both steps are still actively debated.
The first step is commonly believed to involve the generation ofa radical anion by SET from the metal surface to the alkylhalide.216 Subsequently, the radical anion dissociates andrecombines with the metal to generate an organometalliccompound (Scheme 40). The addition of the organometalliccompound to the carbonyl group can be ionic or radical. Theconcerted ionic mechanism involves transfer of two pairs ofelectrons, while the stepwise radical mechanism involved theformation of radical pairs. The radical pairs should be trappedin solvent cages because no dimerization of carbonyl groupswas observed.217 The inversion of configuration at the chiralcenter was observed when chiral alkyl halides were employed inthe reaction, which indicates an SN2 mechanism. Themechanism of formation and addition of Grignard reagents tocarbonyl groups will be discussed in more detail in section3.1.2.In 1982, it was demonstrated that when lithium is used as the
metal reagent, no organolithium adduct was formed. Instead,the radical anion generated or the transient radical pair R··Lireacted directly with the ketyl radical anion formed on thelithium surface as shown in Scheme 41.218 The competitionbetween the organometallic and radical pathways is dependenton the stability of the radical anion or radical pair. The morestable the radical species are, the more favorable the radicalmechanism is, and vice versa. Theoretical calculations alsosupport the formation of the radical anion when saturated alkylhalides are used.219
Historically, due to the high variability of yields, the Barbierreaction was not studied as extensively as the Grignardreaction.91 More recently, interest in the Barbier reaction hasre-emerged, focusing on the application of Barbier-type reactionin aqueous media.91,220 Metals other than Mg and Li were alsoapplied in the Barbier reaction: Zn,221 Sn, Al, Sr,222 In,99b etc.SmI2-mediated Barbier-type reaction was also reported.223
Aqueous Barbier type reaction was reviewed until the year2011.91,220 The application of metallic strontium in Barbier-type reaction was reviewed until the year 2006.222 Barbierreactions find preferential use over the Grignard reaction in thefield of carbohydrate chemistry. Addition of brominatedcarbohydrate derivatives to aldehydes proceeds withoutinefficient sequential protection and deprotection of the freehydroxyl groups.224
Recently, a zinc-mediated Barbier-type reaction for diaster-eoselective synthesis of vicinal amino alcohols was reported.225
Hammett kinetic studies and computational modeling bothpoint away from the radical pathway. Rather, a two-electrontransfer process with a Zimmerman−Traxler transition state isproposed to be the key step for the high diastereoselectivity(Scheme 42).
Scheme 39. Barbier Reaction of Alkyl Halides
Scheme 40. Grignard-type Mechanism of the BarbierReaction
Scheme 41. Radical Pair Mechanism of the BarbierReactiona
aLi = Li·.
Scheme 42. Diastereoselective Synthesis of AminoAlcohols225
At present, no consensus in the field on the mechanism ofBarbier reaction has been reached. Whether the reactionproceeds via a radical or nonradical mechanism is substrate andmetal dependent. Nevertheless, the SET pathway should alwaysbe considered when designing synthetic routes and optimizingBarbier reactions. With variations in metal donor, alkyl, allylhalides, ketones, aldehydes, and imines, the Barbier reaction iswidely applied in synthetic chemistry.3.1.2. The Grignard Reaction. Discovered in 1900 by
Francois Auguste Victor Grignard, the Grignard reaction is theaddition of a Grignard reagent to a carbonyl group (Scheme43).96
In 1972, during investigations on the formation of a Grignardreagent from Mg and alkyl halides, Bodewitz and co-workersobserved the occurrence of radicals by means of chemicallyinduced dynamic nuclear polarization (CIDNP).226 CIDNP is aNMR technique that is usually used to study radicals inreaction. Because the magnetic momentum of an unpairedelectron is 600 times higher than that of a proton, the spins ofprotons are polarized by the unpaired electrons and the 1HNMR signals are enhanced. The CIDNP spectra observed inGrignard reagent formation proved the existence of radicalpair.226 Moreover, it was proposed in 1973 that the radical pairwas generated by SET from Mg to alkyl halides, generatingalkyl halide radical anions, which sequentially dissociate to alkylradials.227 Studies from the Whitesides laboratory also supportthe presence of radical intermediate by trapping the radicalspecies with TEMPO.228 Further studies on the SETmechanism of Grignard reagent formation were carried out ingreat detail in the 1980s to elucidate the mechanism.228a,229 Inall, 10 transition states (TS) were proposed (Scheme 44).
The kinetic profiles for the formation of Grignard reagentsfrom alkyl halides with different organic groups as well as Mgwith different size, purity, and supplier were recorded.229d Therate of the reaction is independent of the structure of the alkylhalide, indicating that neither alkyl cation (Scheme 44, 5),anion (Scheme 44, 4), oxidative addition (Scheme 44, 8), norSN2 (Scheme 44, 7) TS are involved.229d However, the surfacearea of Mg impacts the rate of the reaction, indicating theparticipation of metal−solution interface and thus excluding TS1.229d TS 3 and 6 (Scheme 44) were found to be the mostplausible intermediates.229d To distinguish between these twomechanisms, the rate structure profile of cleavage of C−X bondin alkyl chlorides and bromides by Mg with (t-Bu)3SnH (anISET reagent or AT reagent) and lithium 4,4-dimethylbenzo-phenone ketyl (an OSET reagent) were compared.230 The ratestructure profile of these cleavages showed linear correlation,indicating the similarity of the TS for each of these C−X bondcleavages. No conclusion was made on whether the SETprocess is ISET or OSET (Scheme 45).229d,230 Moreover, the
formation of Grignard reagent from alkyl iodides and bromidesis diffusion controlled or mass transport controlled because therate of reaction in several solvents is inversely proportional toviscosity.229e However, the reaction rate of alkyl chlorides isslower than the rate of diffusion-controlled reactions.229d
Moreover, Whitesides also brought up the issue of the lifetimeof alkyl halide radical anion species. The short lifetime of somealkyl halide radical anion species made it difficult to discusswhether the SET process is concerted with the bond-breakingprocess or not.229a
Because no conclusion was drawn on whether the formationof Grignard reagent is ISET or OSET process, this process willbe described as SET throughout the remainder of this Review.Grignard reagents are mostly monomeric in THF, while they
dimerize in diethyl ether and undergo exchange with associatedspecies, according to the so-called Schlenk equilibrium(Scheme 46).217,231
The mechanism of addition of Grignard reagents to carbonylgroups is nuanced and substrate sensitive.231,232 For primaryalkyl halides, the reaction most probably proceeds via a polarmechanism because the stability of primary alkyl radicals is low.When the substrate is bulky or contains a weak C−Mg bond,the reaction is likely to proceed through a radical mechanism(Scheme 47). A trace amount of transition metal present in Mgused for the production of Grignard reagent is also reported tocatalyze the SET addition of Grignard reagent to ketones. Polarsolvents enhance the stability of the intermediate ketyl radicalanion and hence promote the radical pathway. It is noteworthyto mention, in some of the early mechanistic studies of
Scheme 43. Reaction Scheme of the Grignard Reaction
Scheme 44. Ten Transition States Proposed for GrignardReagent Formation228a,229
Scheme 45. Formation of Radical Intermediates in thePreparation of Grignard Reagents229d,230
Grignard reaction, the isomerization of radicals was used todetect the radical pathway. However, the rate of isomerizationmight be lower than the radical reaction. Hence, while thepresence of isomerization is sufficient to support a radicalpathway, the absence of isomerization does not indicate theabsence of the radical pathway because if the addition rate ofradical to CO is faster than isomerization, then noisomerization product will be detected. Hence, it is proposedthat a chiral Grignard reagent with a stereocenter on C next toMg will solve this problem.233
After 113 years of active mechanistic investigations, there arestill unanswered questions regarding the pathway of theGrignard reaction. Despite this, the application of the Grignardreaction has grown significantly. Current electrophilesemployed in Grignard reactions have expanded beyondcarbonyl groups, to imines, nitriles, borates, oxiranes, sulfoxides.A comprehensive book on advances on Grignard reagents andGrignard reactions was published in 2000.206 There is recentrenewed interest in methods for the preparation of Grignardreagents. Progress on the halogen−metal exchange reactionenables the synthesis of functional Grignard reagents withgroups such as esters, nitriles, iodides, imines, and nitrogroups.234 The advances in preparation and application ofmagnesium carbenoids also open new chemistry for organo-magnesium-mediated synthesis,235 including the geminaldisubstitution of carbonyl oxygens by 2 equiv of Grignardreagents.236
Another application of Grignard reagents is the couplingreaction of Grignard reagents with alkyl, vinyl, or aryl halidesand C−O electrophiles in the presence of a transition metal.237
When nickel or palladium is used, the reaction is calledKumada−Corriu coupling, reported independently by Corriuand Kumada.238 The reaction has attracted great interest bothby the organic and by the polymer synthesis commun-ities.237,239 Although the reaction is believed to follow a two-electron transfer process, there is recent evidence of a radicalcharacter in the oxidative addition step. More details will bediscussed in the section of SET in nickel-catalyzed couplingreactions. Lately, a coupling reaction between a Grignardreagent and aryl iodide was reported without the aid oftransition metal. The reaction was proposed to proceed via theradical-nucleophilic aromatic substitution (SRN1) mechanism(Scheme 48).240 The SRN1 reaction is the substitution reactionof aromatic compounds by a radical chain mechanism. It will bediscussed in more detail in section 3.4.5 for perfluoroalkylhalides and aromatic compounds, respectively. The SRN1reactions of aryl halides with Grignard reagents proceed withgood to excellent yields for 17 aryl iodides (Scheme 49).3.1.3. Kagan−Molander SmI2 Reaction. SmI2 chemistry
was first studied by the Kagan laboratory.241 The addition of
alkyl halides to carbonyl groups occurs in the presence of 2equiv of SmI2. Alkyl bromides, iodides, and tosylates react withaldehydes and ketones producing the corresponding alcohols.The intramolecular reaction was reported by the Molanderlaboratory (Scheme 50).242 The reaction has two versions,depending on whether or not the organosamarium adduct isisolated. The in situ addition variant of the reaction was of
Scheme 47. Mechanism of Grignard Reaction Scheme 48. SRN1 Mechanism of Arylation with GrignardReagents240
Scheme 49. Coupling of Aryl Grignard Reagents with ArylIodides via SRN1 Mechanism240
higher synthetic interest as compared to the reaction whereinorganosamarium was isolated.223
Curran used hexenyl radicals as radical clocks to study thereaction mechanism of radical cyclization mediated by SmI2(Scheme 51). The rates of alkyl radical formation and reduction
of alkyl radicals to carboanions were compared.207,243 It wasconcluded that hexamethylphosphoramide (HMPA) increasesthe reduction rate for both alkyl halides and radicals. Initialaddition of HMPA increases the rate of the reductiondramatically. After the addition of 5 equiv of HMPA, theproduct generated from the carboanion intermediate increases.It is generally believed, in the case of intermolecular
reactions, that both the formation of organosamariumspecies207 and the addition of organosamarium species tocarbonyl groups proceed by SET processes.244 When the SETprocess is involved, qualitatively, the interaction between Smand O is expected to be strong (Scheme 52), while the
interaction between Sm with alkyl halide is weak (Scheme 53).Therefore, it is expected that the former would undergo anISET process, while the latter would probably proceed by anOSET mechanism. Experimental results support this hypoth-esis.Skrydstrup and Daasbjerg laboratories compared the free
energy of the electron transfer of SmI2 to organic electronacceptors (ketones and alkyl halides) with that to known outer-sphere electron donors. Four aromatic radical anions wereemployed to compare with SmI2. They concluded that the SETof SmI2 to acetophenone was an ISET, while the SET of SmI2to benzyl bromide was an OSET with a little inner-spherecharacter.245 In the presence of HMPA, Sm does not exist inSm2+ form; instead, it was proposed to be [Sm(HMPA)4]
2+I2(when 4 equiv of HMPA is present) or [Sm(HMPA)6]
2+I2(when more than 10 equiv of HMPA is present). By using thestopped-flow technique, the Flowers laboratory studied the
kinetics of SET of various Sm species to ketones and alkylhalides. The rate of reduction of ketones was found to beunchanged when different Sm species were used, while the rateof reduction of alkyl halides was found to be dependent on theSm species used. Hence, it was concluded that the SET of Smto ketone is inner-sphere while the SET of Sm to alkyl halides isouter-sphere.246 Skrydstrup and Daasbjerg studied the sameprocess. The energy of electron transfer was compared to theknown energy of electron transfer of radical anions. It wasconcluded that all SET processes are of inner-spherecharacter.247 In a book written after the original publicationsby both Flowers and Skrydstrup, the authors conclude that theouter-sphere character of the reduction of halides decreases inthe order R−I > R−Br > R−Cl. The reduction of carbonylgroup can be considered an inner-sphere process.248 Skrydstrupand Daasbjerg based their conclusions on the energy ofinteraction of SmII with substrates, while Flowers based theirconclusions on the solvent effect. Different methods ofinvestigation of the reaction mechanism led to differentconclusions.After about 26 years since the introduction to organic
chemists, SmI2 is widely used in organic synthesis. As comparedto zero-valence metal reductants, SmI2 reduction is homoge-neous, mild with tunable chemo- and stereoselectivities byadditives and ligands. The ability of Sm to mediate both radicaland anionic processes enabled diverse chemistries includingchemo- and stereoselective functional group interconversion toC−C bond-forming reactions.223,247,249 One important part ofsamarium iodide chemistry is the cyclization reaction widelyapplied in natural products synthesis.250 Other lanthanidesbesides samarium have also been applied to reductivechemistry.111b
The coupling of α-amino acid derivatives with methylacrylates mediated by SmI2 was recently applied for thesynthesis of (−)-Pumiliotoxin 251D and Epiquinamide(Scheme 54).251
The SmI2-mediated cyclization was also applied for thesynthesis of ent-Kauranoid natural products (Scheme 55).252
Scheme 51. Understanding the Active Species in SamariumReduction
Scheme 52. SET of SmIII2 to the Carbonyl Group
Scheme 53. SET of SmIII2 to Alkyl Halide
Scheme 54. SmI2-Mediated Coupling of α-Amino AcidDerivatives with Methyl Acrylates251
Scheme 55. Synthesis of Intermediate for ent-Kauranoid252
3.1.4. SET Reactions of Perfluoroalkyl Halides.Perfluoroalkyl radicals are very important intermediates in thesynthesis of fluorinated organic and macromolecular com-pounds.253 The generation of perfluoroalkyl radicals fromperfluoroalkyl halides includes thermally or photochemicallyinduced homolytic cleavage of C−X (X = I, Br, or Cl) bond,the use of free radical initiators, electrochemical methods,fenton methodology, and SET to perfluoroalkyl halides.254
Historically, the thermally or photochemically inducedhomolytic cleavage of C−X bond was developed prior to theSET-induced C−X cleavage. However, the high temperatureand long photolysis time of this homolysis methodology limitedits use in organic synthesis.254 Generation of perfluoroalkylradicals from the SET process enabled great improvements inthe synthesis of fluorinated compounds over the years.255
William R. Dolbier, Jr. reviewed the structure, reactivity, andchemistry of fluorinated free radicals in 1997.253,254 For acomplete list of fluorinated organometallics and the applicationof fluorinated organometallics, the readers are referred to areview by Burton and Yang.209
Two mechanisms were proposed to account for thegeneration of perfluoroalkyl radicals: the stepwise DETmechanism and the concerted DET mechanism.8 These twomechanisms are outlined in Scheme 56.
The major difference between these two mechanisms is inthe formation of perfluoroalkyl radical anion. In the stepwiseDET mechanism, the perfluoroalkyl radical anion is formedprior to the cleavage of C−X bond and exists as anintermediate, while in the concerted DET mechanism, thecleavage of C−X bond is concerted with the SET step. TheSET to perfluoroalkyl halides was considered as stepwise DETmechanism by Wakselman,255a while the Saveant laboratoryconsidered the mechanism to be a concerted DET mecha-nism.23,35 Recent DFT studies showed that the SET process toperfluoroalkyl halides follows the stepwise DET mechanismboth in the gas state and in the presence of solvents such asMeCN and DMSO.27,256 Hence, all SET of perfluoroalkylhalides in this Review will be treated as proceeding by astepwise DET mechanism. After the generation of perfluor-oalkyl radicals, the perfluoroalkyl radicals add to unsaturatedsystems such as NO bond, alkenes, and alkynes,257 undergoSRN1 reactions with nucleophiles,258 and react with arenes.258
Another important type of the SET reaction of perfluoroalkylhalides is the sulfination and sulfinatodehalogenation reac-tion.259 The reactivity pattern of perfluoroalkyl radicals issummarized in Scheme 57. Each reaction class will be discussedin more detail in sections 3.1.4.1, 3.1.4.2, and 3.3.2.3.1.4.1. SET Additions with Perfluoroalkyl Halides. The
addition reaction of perfluoroalkyl halides induced by SET isshown in Scheme 58.The first report of SET reaction of perfluoroalkyl halides is
on the addition of perfluoroalkyl iodide to an enamine under
UV irradiation.260 Originally, the mechanism was notelucidated. Later, the reaction was found to occur withoutirradiation, while trace amounts of oxygen in the startingmaterial slowed the reaction. This evidence accompanied by theobservation that no reaction took place for ynamines withoutirradiation led the authors to conclude that the reaction is achain process. The chain-initiation process is the SET ofenamine to perfluoroalkyl halides (Scheme 59).261
Later, the transition metal carbonyl complex-initiatedadditions of per- and polyfluoroalkyl iodides and bromides toalkene and alkynes were reported.262 The addition to
Scheme 56. SET Reactions with Perfluoroaklyl Halides
Scheme 57. Reactivity Patterns of Perfluoroalkyl Radicals259
Scheme 58. Addition of Perfluoroalkyl Halides via SET
allylsilanes was also observed.263 The reactivity of perfluoroalkylhalides follows the trend: Rf−I > Rf−Br > Rf−Cl.
262b Zero-valent metals were applied as SET donors to initiate theaddition reaction.264 Solvent effects were also studied. In thecopper-catalyzed addition of perfluoroalkyl iodides to olefins,various solvents were studied in the addition of perfluoroalkyliodide to olefins in the presence of copper.264 It was found thatthe amount of copper did not influence the yield or the productdistribution of the reaction in acetic anhydride. An equivalentamount of hydroquinone relevant to copper stopped thereaction. p-Dinitrobenzene decreased the reaction yield.264
Formation of organocopper species was excluded becauseiodobenzene was recovered almost completely after addition tothe mixture of perfluoroalkyl iodides with copper.264 However,in DMSO, a stoichiometric amount of copper has to be used toobtain a high yield because the SET process in DMSO wastrapped in the solvent cage, and perfluoroalkyl cupric specieswere stabilized by DMSO.264 Other metals or metal complexesincluding Mg,265 Rainey nickel,266 Pd(PPh3)4,
267 NiCl2/Zn/PPh3,
268 and In99a are all capable of initiating the additionreaction of perfluoroalkyl halides to alkenes and alkynes. Forthe mechanistic details of metal mediated addition ofperfluoroalkyl halides to alkenes, ring closure of diallyletheras well as the inhibition effect of radical inhibitors indicate thatthe reaction proceeds by a SET-initiated radical chain process(Scheme 60).265,266,268,269
It is important to mention that when Mg is used, theformation of the perfluoroalkyl Grignard reagent as well as theformation of the perfluoroalkyl radical via SET are bothpossible. The presence of the Grignard reagent can be trappedby acetone. The formations of alcohol products with the alkeneaddition products in THF and nonether solvents werecompared. It was concluded that the reaction of perfluoroalkyliodides with alkenes in the presence of Mg in MeCN proceededexclusively by a radical mechanism because no CO additionproduct was generated. However, in THF, both the COaddition product as well as the CC addition product weregenerated, which led the authors to conclude the coexistence ofboth radical and Grignard reagent species in reactions carriedout in THF (Scheme 61).265
An ESR study of perfluoroalkyl radical failed presumably dueto the short lifetime of the radical.269 However, the radicalcould be trapped by t-butyl nitrone, and the radical producedwas observed by ESR (Scheme 62). The absence of β-H
splitting in the ESR spectrum demonstrated the existence of theRf group. Moreover, the radical formed after the addition ofperfluoroalkyl radical to CC bond was also captured byESR.269
Nonmetal SET initiators include amines,261 sulfur-containingcompounds,270 phosphines,271 and oxidants.272 Oxidants272-induced SET of perfluoroalkyl halides addition was alsoreported. The perfluoroalkyl halide radical cation was proposedto be the reaction intermediate in this case (Scheme 63).
PPh3 was found to be an efficient SET donor forperfluoroalkyl halides. The PPh3-catalyzed addition of per-fluoroalkyl halides to alkenes was reported.271 Sty and 1,3-cyclohexadiene failed to react under these conditionspresumably due to the stability of benzyl and allylic radicals.The results are summarized in Scheme 64.
Light-induced SET of perfluoroalkyl halides addition toaromatic systems was also reported. The mechanism isillustrated in Scheme 65.Perfluoroalkyl halides can also be used in addition to allenes
(Scheme 66), aromatic rings,273 porphyrins,274 as well asfullerenes.275
Neal O. Brace reviewed the syntheses with perfluoroalkyliodides in addition reactions, substitution reactions, andreaction with arenes until the year 1999.257,258,276 Theutilization of perfluoroalkyl halides in the synthesis offluorinated organic compounds prior to May 2013 was alsoreviewed.273a,275,277 Research on perfluoroalkylation reactionsreported with trifluoromethylation reactions will be discussed insection 3.1.4.3. Recent advances in SET of vinylidene fluoridefrom Mn2(CO)10 under photolysis conditions led to the
Scheme 60. Capture of Rf· by Diallylether
Scheme 61. Mg-Induced Addition of PerfluoroalkylHalides265
Scheme 62. Capture of Rf· by Phenyl t-Butyl Nitrone269
Scheme 63. Oxidant-Induced SET Addition
Scheme 64. PPh3-Catalyzed Addition of PerfluoroalkylHalides to Alkenes271
synthesis of well-defined poly(vinylidene fluoride) blockcopolymers.278
3.1.4.2. SRN1 to Perfluoroalkyl Halides. Almost at the sametime as the discovery of SET-induced addition reactions ofperfluoroalkyl halides, the SRN1 reaction involving perfluor-oalkyl halides was discovered.279 This reaction is shown inScheme 67.
Feiring reported the reaction between perfluoroalkyl iodideswith the known SRN1 donor 2-nitropropyl anion (Scheme68).280 The reaction was found to proceed by an SRN1 process.The reaction was carried out with perfluoroalkyl iodides and
lithium 2-nitropropyl anion in DMF and in DMSO, withtetrabutylammonium 2-nitropropyl anion salt in methylenechloride and in benzene, respectively. UV irradiation increasedthe reaction rate, while p-dinitrobezene inhibited the reaction.Primary perfluoroalkyl iodides formed the substitution product,while dimerization took place for secondary perfluoroalkyliodides. Primary perfluoroalkyl radicals are more reactive ascompared to secondary perfluoroalkyl radicals. Substitution ofbenzene was observed as well as the addition to the doublebond of Sty. Amines as well as thiolates were also found to beefficient electron donors in this SRN1 process.281
The reaction of secondary perfluoroalkyl iodides withthiophenol was also reported (Scheme 69).280 This reaction
also follows an SRN1 mechanism. The perfluoroalkyl radicalproduced in this reaction was trapped by norbornene. Thereaction mechanism involves SET from thiolate to perfluor-oalkyl iodide with generation of perfluoroalkyl iodide radicalanion. A dissociative mechanism generates the perfluoroalkylradical. Subsequently, the radical initiates the chain SRN1reaction with phenyl thiolates.Following the report of Feiring, methylviologen was used as
an electron transfer agent to accelerate the generation ofperfluoroalkylarylsulfides.282 Chen reviewed the SRN1 reactionscarried out in their laboratory until the year 1999.255b Bracereviewed the reaction of perfluoroalkyl iodides with nucleo-philes in 2001,258 while Rossi reviewed the SRN1 ofperfluoroalkyl halides in 2002.283 The reaction of perfluoroalkyliodides with sulfur, phosphorus, and selenium containingcompounds was reviewed until the year 2010.275 The synthesisof trifluoromethylthio-substituted building blocks was reportedrecently (Scheme 70).284
Chen’s laboratory observed an uncommon vinylic SRN1reaction in 2006.285 Laboratory light was sufficient to initiatethe reaction. Radical inhibitors such as p-dinitrobenzene as well
Scheme 65. Light-Induced SET Addition of PerfluoroalkylHalides to Aromatic Systems261
Scheme 66. Addition of Perfluoroalkyl Iodides to Allenes
Scheme 67. SRN1 to Perfluoroalkyl Halides
Scheme 68. SRN1 of Perfluoroalkyl Iodide with 2-NitropropylAnion280
Scheme 69. SRN1 of Secondary Perfluoroalkyl Iodides withPhenyl Thiolates280
as hydroquinone interrupted the reaction. The intermediatevinyl radical was trapped and observed by ESR. The reactionmechanism and the products are shown in Scheme 71.
3.1.4.3. SET-Induced Trifluoromethylation. The presence oftrifluoromethyl group in pharmaceuticals, agrochemicals,macromolecules, and functional materials triggered substantialinterest in the trifluoromethylation reaction.286 In 1969,McLoughlin and Thrower reported copper-mediated synthesesof fluoroalkyl-substituted aromatic compounds by heating aryliodide with perfluoroalkyl iodide in the presence of copper inDMSO or DMF at 120−190 °C.287 The reaction was proposedto proceed by formation of perfluoroalkylcopper intermediatesfollowed by reaction of aryl iodide with perfluoroalkylcopperintermediates to generate perfluoroalkyl-substituted aromaticcompounds.287 The highest yield was 95% for perfluoroalkyliodides and 40% for perfluoroalkyl bromides. Trifluoromethy-lation of iodobenezene was reported in 45% yield. Burton andYang reviewed the progress of fluorinated organometallics until1992.209 Grushin and Tomashenko reviewed the progress ofmetal-mediated aromatic trifluoromethylation up to December2010.286 The progress of radical trifluoromethylation was alsoreviewed up to April 2012.288 This section will focus on recentprogress of SET-induced trifluoromethylation reported afterApril 2012.Following a report from MacMillan laboratory in 2009,289
Zakarian’s laboratory published the asymmetric trifluorome-
thylation of N-acyl oxazolidinones.290 The reaction proceededvia Ru-catalyzed radical addition to zirconium enolatespathway. The mechanism as well as the products are listed inScheme 72.290 The chiral auxiliary was then removed byhydrolysis with LiOH/H2O. Treatment of the products withLiAlH4 at −78 °C for 30 min removed the chiral auxiliary in90% yield.
CF3I was used in the first report of metal-mediatedtrifluoromethylation. However, CF3I is a gas at roomtemperature. The difficulty of handling CF3I in a laboratorysetting triggered the development of other trifluoromethylsources.288 Trifluoromethylsulfonium salts are good alternativereagents for CF3I. Ruthenium-catalyzed hydrotrifluoromethyla-tion of unactivated alkenes and alkynes under visible light withUmemoto reagent and MeOH as hydrogen source wasreported.291 Isotope labeling experiments confirmed the sourceof H from the methyl group of CH3OH. Moreover, cyclizationof diene was observed (last row, Scheme 73), confirming theradical mechanism of this reaction.The redox chemistry of trifluoromethyl sulfonium salts was
investigated in anhydrous MeCN, DMF, and MeOH usingcyclic voltammetry. The data generated can be applied to guidethe design of catalytic systems based on photoredox andelectroredox pathways.292 Copper-catalyzed Sandmeyer tri-fluoromethylation reaction using the Umemoto reagent(Scheme 74) was reported.293 The yields ranged from 40%
Scheme 71. Vinylic SRN1 Reaction285
Scheme 72. Asymmetric Trifluoromethylation of N-AcylOxazolidinones Catalyzed by RuCl2(PPh3)3
to 89% for electron-rich as well as electron-deficient anilines.Ketones, amides, CC, esters, ethers, halides, acetals, as wellas triple bonds were tolerated. Heteroaromatic compoundswere also trifluoromethylated in moderate to good yields.These reaction conditions were also applied in intramolecular
cyclization and formation of CF3-substituted heterocycles(Scheme 74).To address the mechanism, the trifluoromethyl radical
generated from the reaction of Umemoto’s reagent with copperpowder was trapped by TEMPO and observed by 19F NMR.On the basis of this data, the authors proposed that thegeneration of trifluoromethyl radical was from SET of copperpowder to Umemoto’s reagent.293
Copper-catalyzed Sandmeyer trifluoromethylation of arene-diazonium tetrafluoroborates was also successful with TMSCF3reagent. A 98% yield was obtained for 4-chlorophenyldiazonium tetrafluoroborates. Moderate to good yields wereobtained for other aromatic and heteroaromatic substrates. Thereaction mechanism is shown in Scheme 75.294
While the copper-catalyzed Sandmeyer trifluoromethylationproceeds by SET pathway, the silver-mediated trifluoromethy-lation of aryldiazonium salts was considered by the Wanglaboratory to proceed by an oxidative addition step involvinghigh-valent Ag species. Moreover, the absence of cyclizationproduct and the observation that nitrobenzene did not impactthe reaction led the authors to conclude that the reaction didnot proceed by a radical mechanism.295 However, the silver-catalyzed trifluoromethylation of arenes was reported toproceed by a radical mechanism. The trifluoromethyl radicalwas proposed to be generated from oxidation of TMSCF3 byAgI and PhI(OAc)2 (Scheme 76).
296
Two recent publications coupled the C−C bond formationwith trifluoromethylation reaction to construct trifluoromethy-lated carbocycles and heterocycles. Sodeoka’s297 laboratoryused Tongi’s reagent as trifluoromethyl source and observedthe formation of five-membered rings and six-membered rings.For some substrates, the six-membered rings were formedexclusively, but the mechanism was not discussed. The trueactive species was not clear to the authors, but a trifluoromethylcation active species was proposed (Scheme 77).The Studer laboratory also used Tongi’s reagent (Scheme
71) to construct 6-trifluoromethyl-phenathridines. The reactionwas proposed to involve a SET-induced radical process.298
Bu4NI was found to be an efficient initiator (Scheme 78). Goodyields were obtained for 23 substrates. The reaction wasinterrupted by TEMPO, and perfluoroalkylated phenathridineswere synthesized as well.298
Copper-mediated trifluoromethylation of aromatic andheteroaromatic compounds using potassium trifluoracetateenabled by a flow system was reported by Buchwaldlaboratory.299 A mixture containing stoichiometric CuI,pyridine mixed with aryl iodide, and potassium trifluoroacetatein NMP was heated to over 200 °C. The reaction was finishedin 16 min and generated over 65% yield for 24 examples. AHammett study was performed to understand the mechanism.
Scheme 73. Hydrotrifluoromethylation of Alkenes andAlkynes Catalyzed by Ru(bpy)3Cl2·6H2O
The positive ρ value found supports the oxidative addition ofaryl iodides on CuCF3 species (Scheme 79).Both CuCF2CF3 and CuCF3 were also applied as
pentafluoroethyl and trifluoromethyl sources for pentafluor-oethylation (Scheme 80) and trifluoromethylation (Scheme81) of aryl and heteroaryl halides by the Grushin group.300 In2013, Grushin’s laboratory published the perfluoroalkylation ofaryl halides with CuCF2CF3. Over 90% yield was observed by19F NMR for 31 examples, including aryl and heteroarylexamples (Scheme 80). The trifluoromethylation reaction using
CuCF3 was also reported. The scope, limitation, andmechanism of the trifluoromethylation reaction were inves-tigated.300a Up to 73 aryl halides were converted to thecorresponding trifluoromethyl substituted arenes and hetero-arenes. Gram-scale products were isolated. This mechanisticstudy suggested that this reaction does not follow a radicalmechanism.3.1.4.4. Synthesis of Sequence-Controlled Self-Organiz-
able Semifluorinated Oligomers by SET. A sequenced-controlled multiblock copolymer containing perfluorinatedand perhydrogenated segments was demonstrated to formliquid crystal structures due to the phase segregation of itsfluorinated and hydrogenated segments.301 The synthesis ofsequence-controlled self-organizable semifluorinated oligomerswas achieved by both radical polymerization initiated by AIBNand by SET polymerization induced by Pd(Ph3)4.
301
Pd0(PPh3)4 initiated the polymerization by SET of the α,ω-diiodoperfluoroalkane that led to the formation of α,ω-diiodoperfluoroalkane radical anion, which was followed byC−I bond cleavage. The propagation steps led to the formationof oligomers with perfluorinated and perhydrogenated seg-
ments. Iodine atom transfer to the oligomer radical terminatesthe chain process (Scheme 82).301 As compared to theuncontrolled AIBN initiated radical polymerization carriedout at 60−120 °C, the Pd0-mediated process was carried out atroom temperature, with low concentration of radical speciesduring the polymerization process and no H-abstraction by thehighly reactive perfluoroalkyl radicals.301 The reduction of theiodine groups was carried with Bu3SnH.
301
By using predetermined and stoichiometric ratio of the twomonomers, the structure of the chain ends was perfectlycontrolled. Copolymers with either olefinic or −CH3 chainends were synthesized (Schemes 83 and 84).301
3.1.4.5. Synthesis of Semifluorinated Self-AssemblingDendrons by SET. The introduction of semifluorinated alkylchains in self-assembling dendrons and dendrimers reduced thenumber of generations required to induce their self-assemblyinto columnar supramolecular structures from 2 or 3 to 1. Adramatic stabilization of the hexagonal columnar assemblies wasobserved upon fluorination.302 Semifluorinated dendrons weresynthesized by radical addition of perfluoroalkyliodine toalkenes via a SET mechanism (Scheme 85).303
Semifluorinated tapered monodendrons with crown etherapexes self-assemble into supramolecular columns that self-organize into hexagonal columnar periodic arrays (Scheme86).303 The simplest class of rod-like mesogens forming classicliquid crystalline phases and containing a single benzene groupwas also elaborated via semifluorination.305
Incorporating donor or acceptor groups to the apex of thedendrons led to the formation of columnar structures withdonors, acceptors, and donor−acceptor complexes arranged inπ-stacks structure, which showed dramatically increased chargecarrier mobilities.306 Janus dendrimers synthesized fromsemifluorinated dendrons and perhydrogenated dendronswere also prepared and were demonstrated to self-assembleinto bilayer pyramidal columns.307 These semifluorinated Janusdendrimers also self-organize into vesicular columns thatdecrease the length of the supramolecular column when the
Scheme 81. Trifluoromethylation of Aryl and HeteroarylIodides and Bromide by CuCF3
300a
Scheme 82. Mechanism of Pd(0)-Catalyzed SET Copolymerization of α,ω-Diiodoperfluoroalkanes with α,ω-Dienes toSequence-Controlled Semifluorinated Oligomers301
temperature is increased, behaving as reverse thermalactuators.308 The mechanism of formation of reverse thermalactuators was proposed to be due to the reduction of column-to-column interdigitation mediated by the increased flexibilityof fluorocarbon segments at higher temperatures.308
3.1.4.6. Functionalization of Poly(tetrafluoroethylene) andOther Fluorinated Polymers by SET. Because of the highdissociative energy of the C−F bond, poly(tetrafluoroethylene)(PTFE) is inert to acids, bases, as well as oxidants. Therefore,the functionalization of PTFE and other perfluorinatedpolymers is very challenging. However, PTFE can be reducedand functionalized by SET. The SET donors used in theseexperiments can be classified into the following four categories.The first category involves solvated electrons. Conditions
reported include: alkali metals in liquid anhydrous ammonia,309
Li or Na with Hg,309,310 Mg in ammonia assisted byelectrochemical method,311 and Hg in ammonia underirradiation.312 The reduction carried out with alkali metals inliquid ammonia provides the harshest conditions. The PTFE
was left with a black surface, which was proposed to be anamorphous carbon surface after removal of the metal fluoridesalts.311 Mg in ammonia provides milder conditions andrequires the assist of electrochemical methods to dissolve theMg. The surface obtained after treatment is less destroyed ascompared to the surface after treatment with Na inammonia.311 The mechanism of reduction by metals inammonia was studied and was proposed to be SET concertedwith F atom abstraction (Scheme 87).312,313
Another method for the reduction of PTFE is theelectrochemical method.314 The mechanism is also a SETreduction mechanism.In 1984, McCarthy’s laboratory reduced the PTFE surface
with benzoin dianion.315 The process was proposed to proceedvia a SET mechanism (Scheme 88).The surface generated from the reduction of PTFE with
benzoin dianion is gold colored as compared to the blackcolored surfaces obtained from reduction by Na/NH3.
315
Spectroscopic methods confirmed the chemical composition ofthe reduced surface as cross-linked polymeric carbon containingC−C single, double, and triple bonds, fluorine and hydrogen,and a small amount of oxygen.316 The reduced surface can thenbe functionalized including bromination, chlorination, as well ashydroboration.316 Other fluorinated polymers such as Teflon-FEP (copolymer of TFE and hexafluoropropylene), Teflon-PFA (copolymer of TFE and perfluoro(propyl vinyl ether)),and poly(chlorotrifluoroethylene) were found to be reduced bybenzoin dianion. However, Teflon-AF (copolymer of TFE andperfluoro-2,2-dimethyl-1,3-dioxole) was found to be inert underthese reduction conditions.317
Last, amine, thiol sodium salts, as well as phenol sodium saltswere found to be effective electron donors for photochemicalmodification of PTFE surfaces.318 The mechanism was
Scheme 83. Synthesis of Olefin-Terminated Semifluorinated Polyethylenes301
Scheme 84. Schematic Representation of (a) the SB Phase of4-6/0/0(100/0/0)-6/0/0(100/0/0) Copolymer and (b) theHexagonal Columnar (Φh) Phase of 4-6/8/10(33/33/33)-4/6/10(29/29/29)301
Scheme 85. Synthesis of Semifluorinated Self-Assembling Dendrons by SET304
proposed to be SET from the excited amine to PTFE.319 Themixture of benzophenone and sodium hydride was also used asan effective reductant for surface modification of PTFE underUV irradiation.320
3.1.5. Wurtz Coupling. In 1855, Charles-Aldolphe Wurtzdiscovered the coupling of two alkyl halides in the presence of
sodium (Scheme 89).10 When one aryl halide is coupled withone alkyl halide, the reaction is called the Wurtz−Fittig
reaction. The coupling of two aryl halides is called the Fittigreaction. The original Wurtz coupling is heterogeneous andprovided low yields. Only homocoupling of alkyl halide waspossible because the reaction is not selective. Moreover, thealkyl radical generated during reduction rearranges. When arylhalides are involved, the Wurtz−Fittig coupling usually gives
Scheme 86. Self-Assembly and Co-Assembly of Semifluorinated Dendrons Contaning Electron Donor, Electron Acceptors, andOther Functional Groups304
Scheme 87. Mechanism of Reduction of PTFE by Metals in Ammonia312,313
Scheme 88. Reduction of PTFE by Benzoin Dianion viaSET315
increased yields because the aryl radical or radical anion doesnot rearrange. For the history of the synthesis with alkyl andaryl derivatives of alkali metals, the readers are referred torecent reviews.146
The first step of Wurtz reaction was proposed to be thegeneration of organosodium compounds. SET from sodium toalkyl halides generates an alkyl radical. The alkyl radical thenreacts with another sodium atom to generate organosodiumcompounds. The organosodium species have been trapped byelectrophiles such as carbonyl groups.146a The mechanism forthe second step is controversial. Two kinds of mechanismswere proposed: nucleophilic substitution and a radicalmechanism. The attack of organosodium species to alkyl halidecan be considered as an SN2 or an SN1 process via transfer oftwo electrons. This mechanism is supported by the observationof inversion of stereochemistry in reaction of benzylic lithiumreagents with chiral secondary halides.321 Another mechanismis the generation of radical pairs in the solvent cage fromorganosodium species with alkyl halides. Because aryl halidesdo not undergo SN1 or SN2 pathways, reactions involvingcoupling of aryl halides with organosodium species mustprocess via a radical mechanism (Scheme 90).
An elegant study published in 1975 demonstrated that theradical mechanism is more plausible in the coupling of alkylhalides.322 In this study, it was shown that the reaction ofneopentyl iodide and pentyl iodide gives product ratios ofdecane, 2,2-dimethyloctane, and bineopentyl of 1.2:1.7:1.1, veryclose to the statistical prediction (1:2:1) if both species are ofthe same reactivity. However, considering the steric hindranceof neopentyl group, it is well established that the SN2 reactionof neopentyl iodide is 4 times slower than that of the pentyliodide. Hence, the simple SN2 mechanism is ruled out.Nevertheless, direct mechanistic support for the radicalpathway is not yet available.Because of the development of transition metal-catalyzed
coupling reactions, the Wurtz reaction has fallen out of favorover time in synthetic applications. Recent developmentsinclude changing the reaction from heterogeneous tohomogeneous by addition of catalytic amounts of tetraphenyl-ethylene,323 increasing reaction yield by application of ultra-sound324 or microwave,325 and replacing sodium with othermetals including Li, Zn, Fe, Cu, In, etc.326 When lithium isemployed, recent developments on lithium halide exchange alsoincrease the utility of Wurtz−Fittig reductive coupling as wasdemonstrated in the preparation of isoindolones by lithium−iodide exchange327 followed by Wurtz−Fittig coupling(Scheme 91).326
Today the most important synthetic application of Wurtzcoupling is most probably in the synthesis of polysilanes andpolystannanes.328 The HOMO−LUMO band gap of poly-silanes is around 3−4 eV and shows optoelectronic absorptionin the near-UV region.329 Early reports on polysilanes synthesisused a mixture of dichlorosilane with molten sodium inrefluxing toluene (Scheme 92).328a
These high-temperature syntheses always result in productswith trimodal molecular weight distribution. Efforts have beenmade to find reaction conditions that lower the reactiontemperature as well as functionalize the resulting polysilanes.329
Polysilanes modified with a dansyl fluorophore were synthe-sized, and the photophysics was studied. This polysilane wassynthesized by the Wurtz coupling reaction and had weight-average molecular weight of 15 400 and molecular weightdistribution of 2.46. The product polysilane was then modifiedby condensation reaction of dansyl amines and gave productswith weight-average molecular weight of 7800 and Mw/Mn of2.09.330
3.1.6. The Muller−Rochow Process for Cu0-CatalyzedSynthesis of Dichlorodimethylsilane. The synthesis ofchloromethylsilanes by reacting alkyl halides with silicon metalwith a catalytic amount of Cu0 at 250−300 °C at 2−5 bar iscalled the Muller−Rochow process, direct process, or directsynthesis (Scheme 93).331 It was discovered independently by
Muller and Rochow in the 1940s104,332 and is currently used inthe industrial synthesis of organosilicon compounds.331a In theoriginal publication, Rochow achieved a yield of 70% forMe2Cl2Si. It was also recommended to run the reaction with acatalytic amount of Cu0 to lower the reaction temperature andavoid the pyrolysis of alkyl radicals.104 Ag was reported to bemore reactive than Cu0 in the synthesis of phenylchlorosi-lanes.332
The mechanism of the reaction was not clear. Initially, duringRochow’s study, Cu0 accelerated the disappearance of Si, andCu0 was removed faster when Si was present.333 CuCl wasfound after the removal of Cu0 by alkyl halides.333 Combining
Scheme 90. Mechanism of Wurtz Coupling
Scheme 91. Syntheses of Isoindolones by Wurtz Coupling326
Scheme 92. Synthesis of Polysilanes by Wurtz Coupling
the evidence of products from pyrolysis of alkyl radicals, atentative mechanism was proposed (Scheme 94).333 However,considering CH3Cu decomposes at below 0 °C,210 and that thereaction is carried out at 300 °C, the existence of CH3Cu isdoubtful.
Research on the mechanism of the direct process prior to1975 was mostly described in Russian language reports. Thisprogress is summarized in a review.334 The involvement oforganic radical species was confirmed by kinetic studies. Cuactivates organic halides and provides CuCl, a Cl atom-transferreagent to Si.334 A Cu−Si alloy structure was also proposed toaccount for the acceleration effect of Cu0 in this reaction.334
Considering the mechanism of the Ullmann reaction, the Cu0
might participate in the generation of radicals (Scheme 95).
Silylene was proved to be the intermediate in the directprogress as silylene was trapped by butadiene and detected bymass spectrometry (Scheme 96).335
Although the mechanism of the Muller−Rochow process isstill not clear, it is applied in industry on a large scale as themost efficient source of raw materials for silicone derivatives.335
Element germanium also reacts in a similar way as Si andorganogermanium compounds can be synthesized in a similarway as in direct synthesis.336 Methanol vapors also react withsilicon and lead to trimethoxysilane with high selectivity.337
New approaches to silicone synthesis enable the preparation ofSi-based dendrimers,338 polymers, and graft copolymers.339
3.1.7. The Preparation of Synthetic Estrogens Led tothe Discovery of Condensation by Reductive Dehaloge-nation Mediated by Metals. In 1936, the biological activityof estrogens led to interest in the preparation of syntheticestrogens.340 Historically, estrogens were synthesized byFriedel−Crafts reaction, Grignard reaction, and retro-pinacolrearrangement, etc.341 Later, reductive dehalogenation con-densation reaction was applied in the preparation of protectedsynthetic estrogens.To our knowledge, the first condensation of benzyl chloride
by Cu0 powder was reported in 1884 at 100 °C (Scheme97).342
This reaction was further modified by Oda’s laboratory usingiron powder in boiling water, a good solvent for SET. The yieldobtained was around 30% for benzyl chloride (Scheme 98).343
For substituted benzyl chloride, the yield was as low as 18%.
The condensation via reductive dehalogenation method wasdemonstrated to be efficient in the synthesis of protectedestrogens in one step (Scheme 99) albeit with the low yieldsobtained.344
However, when Fe powder reduced by H2 was used for thisreaction, the yield more than doubled from 15% to 40%(Scheme 100).345 The reductive coupling method was later
Scheme 94. Tentative Mechanism for the Muller−RochowProcess333
Scheme 95. Revised Mechanism for the Generation ofRadical in the Direct Synthesis334
Scheme 96. Intermediates in the Direct Synthesis335
Scheme 97. Condensation by Reductive Dehalogenation ofAlkyl Halides by Cu0 Powder342
Scheme 98. Condensation by Reductive Dehalogenation ofAlkyl Halides by Fe Powder343
Scheme 99. Synthesis of Protected Estrogens via ReductiveDehalogenation344
used for the synthesis of protected estrogens via other reducedmetals and alloys including copper (Scheme 101).345,346
The mechanism of this condensation reaction wasexamined.347 A radical pathway generated from SET wasproposed to account for the formation of bibenzyl. Anthracenewas proven to be a good radical trap, while phenanthrene wasinert to radical substitution.348 Treating anthracene with iron inbenzyl chloride produced substituted anthracene, indicating theformation of benzyl radical. Replacing anthracene withphenanthrene failed to produce any benzyl-substitutedphenanthrenes. These results led the authors to conclude thatthe reductive dehalogenation proceeded via a radical mecha-nism.347b
3.1.8. Reductive Dehalogenation of Alkyl HalidesMediated by Zero-Valent Metals. Halogenated organiccompounds are toxic and persistent polluants of the environ-ment. For example, hydrochlorofluorocarbons are known todestroy the ozone layer and will be eliminated in the U.S. bythe year 2030. Dichlorodiphenyltrichloroethane is nonbiode-gradable and toxic to birds and banned by the EnvironmentalProtection Agency in the U.S.349 The study of the mechanismof reductive dehalogenation facilitates the understanding ofaerobic and bacterial degradation of halogenated compounds inthe environment and also facilitates the development of noveltechnologies for the elimination of halogenated compoundsfrom the environment.350 The reductive dehalogenationreaction by zero-valent metals and cyclization reactionsmediated by reductive dehalogenation will also be discussed.Traditionally, cyclization is accomplished by (t-Bu)3SnH in thepresence of AIBN. However, the toxicity and difficulty inpurification of organotin reagents hinder the application of (t-
SmI2,45b and ruthenium-catalyzed cyclization45c reactions were
reported and reviewed extensively. Hence, they will not bediscussed in this section. However, zero-valent metals also showreactivity in cyclization, but their recent chemistry was notreviewed. To our best knowledge, the most recent review onSmI2, Fe(CO)5, and Mn2(CO)5-mediated reductive dehaloge-nation, addition to double bond, and telomerization processeswas by Terent’ev and Vasil’eva until the year 1994.352 Hence,we will review here subsequent progress in this field.In 1990, the Tezuka and Imai laboratory reported the
generation of copper carbenoids from copper metal and gem-dichlorides in DMSO (Scheme 102).353
The generation of CuCl2(DMSO)2 was observed by IRspectroscopy. Other metals such as Ti, V, Mg, Fe, Co did notparticipate in this reaction. Lower yields were obtained whenCuCl or CuBr were used. CuCl2 was not reactive under thesame reaction conditions. DMAc, HMPA, and DMF are alsoeffective solvents for this reaction.353 The reaction conditionswere also applied for the polycondensation of coppercarbenoids (Scheme 103).
These experiments suggest the possibility of Cu powder-mediated reductive dehalogenation and cyclization. Othermetals such as Ni and Fe were found later to be reactive inreductive cyclization reactions.354 The cyclization reactionsmediated by Ni0/AcOH were proposed to proceed via a SETprocess. The radical mechanism was demonstrated by trappingthe radical with TEMPO (Scheme 104).Ghelfi laboratory reported the CuBr/Fe0 promoted olefin
alkylation by α-Br-α-Cl carboxylates and esters at 25 °C(Scheme 105).59b,355 The reaction rate was compared to thereaction mediated by Cu0, Fe0, and FeBr2. Only Fe
0 was foundreactive in mediating the addition reaction. It was proposed thatthe role of CuBr was to electrochemically activate the Fesurface. The reaction was proposed to proceed via a SETmechanism to generate the alkyl radical, followed by addition toCC and Br atom transfer.355 Heating the reaction mixture to80 °C in arenes increased the reaction rate, and Fe0 wassufficient to initiate the radical addition.354b,356
Besides the radical addition reactions, CuBr/Fe0 alsopromoted homocoupling as well as dehalogenation of methyl2-Br-2-Cl-carboxylates (Scheme 106).357
The observation that monomers such as ethyl methacrylateformed oligomers supports the radical chain mechanism of theaddition reaction. Fe0-promoted addition of CCl4 and CCl3Brto olefins was reported as well (Scheme 107).358
Scheme 100. Condensation of α-Halogenated Arylalkaneswith Metal Powders in Hydroxylated Media345
Scheme 101. Synthesis of Protected Estrogens via OtherReduced Metals and Alloys345
Scheme 102. Generation of Copper Carbenoids fromCopper Powder with gem-Dichlorides in DMSO353
Ferrocene was found to be an effective catalyst for theaddition of 2,2-dichloro-carboylates to alkenes.359
With the development of intermolecular addition, theintramolecular cyclization reaction was discovered. The radical
cyclization was promoted by Fe0/FeCl3 (Scheme 108) orCuCl-TMEDA.360
The Ghelfi laboratory also reported the reductive radicaladdition of 2,2-dihalocarboxylates to carbonyl compoundspromoted by Zn.361 A preliminary study by Sakuma andTogo showed In- and Zn-mediated ring expansion.99c Thereaction was proposed to proceed via SET generation of alkylradical and radical ring expansion. Yields were moderate togood for 29 examples (Scheme 109).
Following these preliminary data, the authors reported theZn-mediated cyclization reactions in 2004 and 2005 (Scheme110).362
The reductive dehalogenation and cyclization by amine isdiscussed in sections 3.5.1 and 3.5.2.
3.1.9. Reductive Dehalogenation by Radical Anions.The reduction of aromatic hydrocarbons by alkali metal wasobserved as early as 1867.163 However, the dark color species insolution was not understood until Weissman and associatesverified the radical anion formation through electron transferprocesses (Scheme 111).93,363
Some of the commonly used radical anions of aromatichydrocarbons include sodium naphthalene radical anion andlithium biphenyl radical anion. They are used in living anionicpolymerization as well as reduction reactions.170,364 Thereductive potential of naphthalene radical anion is comparableto that of the alkali metals.169 The application naphthaleneradical anion in living anionic polymerization will be discussed
in section 4.2.2. This section will discuss the reductivedehalogenation by aromatic hydrocarbon radical anions.The Sargent group studied the reaction between aromatic
radical anions with alkyl halides in 1966. The dehalogenationand the dimerization products were detected by gas-phasechromatography. The mechanism for the formation of theseproducts was proposed to be SET (Scheme 112).365 Thehomogeneous SET mechanism was confirmed by the study ofthe Garst laboratory.366
The alkylation of naphthalene radical anion was alsoobserved. The formation of the alkylation product wasproposed to follow a SET mechanism (Scheme 113).367
Not only do alkyl halides react with sodium naphthaleneradical anion, aryl halides also participate in these reactionsthrough SET as well.368 Garst reviewed the electron transferbetween naphthalene radical anion and alkyl halides until theyear 1971.369 Holey reviewed the reactions of the radical anionsand dianions of aromatic hydrocarbons.169 A syntheticapplication of the SET of aromatic hydrocarbons to alkylhalides is provided in section 3.2.3.1.3.1.10. Nickel-Mediated Cross-Coupling of Alkyl
Halides. The nickel-catalyzed enatioselective Negishi couplingof unactivated secondary alkyl halides was reported by Fu.370
The reaction conditions and selected products are listed inScheme 114.
Because the process is stereoconvergent, the racemic startingmaterial being converted to the enantiopure product, theauthors made the assumption that radical species are generatedin this reaction.370 Later, mechanistic studies were carried outto understand the effects of ligand structure on the electronicstructure and reactivity of nickel catalysts in alkyl−alkylcoupling reactions.371 No isotope scrambling was observed inthe labeling experiments, contradicting the ESR observedradical anion of the π system single electron species.371 Toclarify this discrepancy, DFT calculations were also carried outto study the Negishi alkyl−alkyl coupling reactions.372 TheDFT study showed that the reaction includes four steps. In thefirst step, iodine transfers via a SET mechanism occurs,followed by radical addition, reductive elimination, andtransmetalation (Scheme 115), thus confirming that the ESRexperiments are correct.372
The cross-coupling reaction was also applied for cascadecyclization and cross-coupling of iodoalkenes with alkyl zinchalides (Scheme 116).373 The reaction mechanism wasinvestigated by kinetic studies and DFT calculations.373 Thereaction mechanism was proposed to be a radical process.373
Recently, a study carried out by Fu’s laboratory investigatedthe Suzuki coupling of unactivated tertiary alkyl halides witharyl-BBN catalyzed by nickel (Scheme 117).374
To account for the formation of diastereomeric cross-coupling products from a single diastereomer of a tertiary alkylhalide, a radical mechanism was proposed.374 An ISET pathway
Scheme 110. Zn-Mediated Cyclization362
Scheme 111. Generation of Naphthalene Radical Anion viaSET
Scheme 112. Reaction of Alkyl Halides with SodiumNaphthalene Radical Anion365
Scheme 113. Mechanism of Alkylation of NaphthaleneRadical Anion367
Scheme 114. Enantioselective Negishi Reactions of BenzylHalides370
was proposed by Fu as the intermediate step for oxidativeaddition of alkyl halides to NiI species (Scheme 118).374
3.1.11. Early Work on Low-Valent Metal-MediatedRadical Polymerization. The metal-mediated living radicalpolymerization has been reviewed extensively since the firstreports of ATRP, SET-LRP, SET-DTLRP, and other metal-mediated radical polymerizations.5−8,78,375 However, thissection will only cover earlier publications and reviews.To our knowledge, most probably the first application of Cu0
powder and benzyl chloride in the polymerization of Sty,methyl methacrylate, and vinyl acetate involves a sealed glass
tube heated to 70 °C reported in 1954 by Furukawalaboratory.376 The conversion and the degree of polymerization(the number of monomer repeat units in a polymer chain, DP)and the rate constant of polymerization increased linearly withthe reaction time, indicating some potential living polymer-ization character.376 A living polymerization is a chainpolymerization accompanied by negligible extent of termination(bimolecular termination in the case of radical polymerization),disproportionation, and chain-transfer reactions. The amount ofcopper as well as benzyl chloride did not impact the conversionor DP of the resulting polymer. The active species wereproposed to be organocopper species. Cu0 and CuIX were alsoused to catalyze the polymerization of vinyl monomers initiatedby diazonium salts in the presence of Na2S2O3.
377 Thepolymerization was proposed to proceed via a radicalmechanism.377 It was observed that this polymerization didnot happen in the absence of copper or diazonium salt. Thepolymerization proceeded slowly when only copper anddiazonium salts were used. A combination of copper, diazoniumsalt, and sodium thiosulfate provided for a much more rapidpolymerization. Combining these two pieces of evidencecollected from Ullmann and Sandmeyer reaction variants,both of these two polymerizations can now be explained by aSET-induced radical polymerization in the absence ofdisproportionation of CuI species. The mechanism is shownin Scheme 119.In 1965, it was reported that other transition metal colloids
including V, Cr, and Co are effective catalysts for thepolymerization of vinyl monomers in the presence ofCCl4.
378 Raney metals (Ni, Fe, Co) with organic halides
Scheme 115. Mechanism for Nickel-Catalyzed Alkyl−AlkylCoupling372
Scheme 116. Nickel-Catalyzed Cyclization and Cross-Coupling of Alkyl Halides373
Scheme 117. Suzuki Cross-Coupling of Tertiary Halides withAryl-BBN374
Scheme 118. ISET Generation of Alkyl Radicals
Scheme 119. Mechanism of Polymerization Initiation by Cu0
including CCl4, BnCl, n-C4H9NCl2, t-C4H9OCl, C6H5SCl, andCH3SiCl3 were also effective in the polymerization of MMAand Sty.379 Diamines, diols, and organic halides increase thepolymerization rate.380 Commercially available metals were alsoused in the polymerization and were compared to activatedmetals.381 It was found that commercial metals were ineffectivein polymerization of MMA or Sty with organohalides inbenzene. This indicated the importance of an active metalsurface in polymerization. Only metal0 was effective incatalyzing the polymerization other than metal oxides.Regarding the efficiency of organohalides, it was found that
CCl4 is more effective than CHCl3, while CHI3 is moreeffective than CHBr3 when Raney nickel was used as catalyst.
382
The rate-determining step of the polymerization was proposedto be a SET step (Scheme 119).382 Evidence for a radicalmechanism includes the inhibiting effect of nitrobenzene aswell as hydroquinone. Nickel chloride was isolated when Raneynickel was used to induce the polymerization, indicating thegeneration of radical initiator via SET mechanism catalyzed byNi0 rather than by Ni chloride.382 The cationic polymerizationof isobutyl vinyl ether was also initiated by metal/organohalidesystems.382
The choice of solvent also impacts the radical polymer-ization. The radical polymerization of MMA in DMF andDMSO was faster than reactions carried out in benzene.Moreover, when commercially available metals that wereinactive in benzene were used for polymerization in DMFand DMSO, the polymerization occurred. DMSO was provento be the best solvent, while the use of MeCN resulted in nopolymerization.383
Not only metal powders, but zero-valence and low-valencemetal complexes also catalyzed the polymerization of vinylmonomers. Bamford’s laboratory reported the polymerizationof MMA catalyzed by a variety of metal carbonyl complexeswith CCl4 initiator.112 The metal complexes used include:Cr(CO)6,
112 Mo(CO)6, W(CO)6,384 Mn2(CO)10, CpMn-
(CO)3, Cp*Mn(CO)3,385 Ni(CO)4,
386 and Co4(CO)12.387
The polymerization was proposed to proceed via a SET-initiated radical mechanism and was strongly inhibited byCO.388 The reaction rate was independent of the concentrationof CCl4 once the concentration of CCl4 increased to a certainamount. Incorporation of 14C in the polymer chain when14CCl4 was used indicates that Cl3
14C· radical was generated asan initiator for the polymerization (step i, Scheme 120).388 Theisotope incorporation experiment confirmed 100% rate of14CCl3 chain end incorporation. Chain-transfer reaction of thepropagating radical to CCl4 led to −Cl polymer end group(step iii, Scheme 120). Chain-transfer reaction of propagatingradical to another chain or solvent led to −H polymer chainend group (steps v and vi, Scheme 120).Moreover, when polyvinyl trichloracetate was used as
initiator, a grafted polymer or graft copolymer (a branchedpolymer with side chains having different features, constitu-tionally or configurationally, from the main chain) wasgenerated instead of a homopolymer. These results supportthe mechanism of radical polymerization initiated by SET frommetal complex to perhaloalkane (Scheme 121).388 Polymer-ization initiated by Mo(CO)6 and CCl4 carried out in differentsolvents showed different characters. In inert solvents such asbenzene and cyclohexane, the solvent only shows a dilutioneffect. However, when the solvent is capable of coordinating
Scheme 120. Mechanism of Zero-Valent Metal Complex-Catalyzed Radical Polymerization
with the metal, such as ethyl acetate, dioxane, acetic anhydride,and benzonitrile, the solvent replaces CO and shows anassisting effect in the activation of CCl4.
389 Light was shown toincrease the rate of the polymerization.390
Not only metal carbonyl ligand complexes could be used ascatalysts. The generation of free radicals from CCl4 withMo(CNPh)6 and W(CNPh)6 was also reported.392 Rapidpolymerization of MMA was observed even at room temper-ature when Ni(PPh3)4 or Ni(CO)4 and CCl4 mixtures wereused to initiate the polymerization.393 Moreover, PPh3 did notshow an inhibiting effect to the radical polymerization as didCO. Hence, the polymerization of MMA at room temperatureis more rapid when Ni(PPh3)4 was used as compared to therate of polymerization when Ni(CO)4 was used.393 Fordinuclear metal carbonyl complexs, such as Mn2(CO)10,photolysis394 or thermolysis393 produces [·Mn(CO)5], whichabstracts a halogen atom from initiator. In 2008, the well-known Mn2(CO)10-mediated polymerization of vinyl mono-mers was re-examined. LRP of VAc, MA, and Sty catalyzed byMn2(CO)10 under photolysis conditions was reported.395
Polymers with Mw values up to 105 were synthesized in acontrolled manner by degenerative iodine transfer mechanism(Scheme 122) at 40 °C in a reaction time of 2 h.
The polymerization only proceeds in the presence of lightand stops with light shielding. This work inspired a verycomprehensive investigation of Mn2(CO)10-photomediatedLRP of vinylidene fluoride via iodine degenerative transferwith up to 43 initiators and 41 solvents.278 The reactionconditions were mild, 40 °C, and varous solvents includingwater and alkyl carbonates were used. Iodine degenerativetransfer dramatically suppressed head-to-head defects commonto conventional vinylidene difluoride free radical polymer-ization. The total iodine functionality was higher than 95% andenabled the synthesis of block copolymers with Sty, butadiene,VC, VAc, MA, and AN.278
In 1990, after the proposal of the initiator-transfer agent-terminator (iniferter) concept by Otsu for living radicalpolymerization,396 reduced nickel/halide systems were usedas redox iniferters. The mechanism for the polymerization wasproposed as in Scheme 123.397
The termination of the monomer chain with X is of essentialimportance to the living character of the polymerization. Ni0
generated from chain transfer reinitiates the terminatedpolymer. The concept was tested with polymerization of Styby reduced Ni and benzyl chloride as monofunctional redoxsystems and p-xylene dichloride as a bifunctional redox system.The polymerization showed a linear relationship betweenconversion and reaction time regardless of the initiator systemused. Moreover, block copolymers between MMA and Sty were
synthesized in 91.4% yield.397 Otsu discussed the iniferterconcept in great detail in a more recent highlight.398 Thecatalysts, initiators, as well as monomers used in zero-valencemetal-mediated LRP prior to 1995 are summarized in Table 3.A list of radical polymerizations using metal complexes as wellas low-valence metal salts is provided in Table 4.
3.1.12. Radical Polymerization Catalyzed by CuII andOther High-Valence Metal Cations. In the early 1960s,Kimura, Takitani, and Imoto demonstrated that several fibers,such as cellulose fibers including cotton, rayon, ramie, silk, andsynthetic fibers including vinylon, polyacrylonitrile (PAN),Nylon-6, and polyethylene terephthalate (PET), suspended inan aqueous solution can initiate the polymerization of MMA insignificant amounts at 90 °C in about 2 h.411−413 Thismethodology was called “uncatalyzed polymerization”.414 Thepresence of water was necessary in all cases. It was found thatthe presence of hydrophilic macromolecules containing variousfunctional groups, such as phosphoryl, sulfone, carboxylate,amide, aldehyde, etc., was required to provide significantpolymerization. Surprisingly in the case of silk, the conversionwas 99%. Later, in 1970, the same group found that in all ofthese cases the presence of a trace amount of CuII or othermetal ions was responsible for this polymerization.415 It wasalso demonstrated that under similar conditions other metalcations, such as CuI, FeII, FeIII, NiII, SnIV, HgII, are also efficientin initiating the polymerization of MMA and Sty.416 The radicalmechanism of the reaction was confirmed by using radicalscavengers, which can completely suppress the polymerization.While the polymerization of acrylates in the presence of silkand cellulose was effective, Sty could not be polymerized. Theauthors explained this selectivity based on hard and softhydrophobic areas of the macromolecular fibers and themonomers. Although traces amount of CuII facilitate thepolymerization, addition of excess CuII decreased the reactionyield due to deactivation of the propagating radical chain(Scheme 124).According to the authors, in this polymerization technique,
CuII forms a complex with the macromolecular fiber. It isrequired that this complex contains two vacant sites. The CuII
ion does not change its valence during the polymerization. Theauthor proposed two plausible mechanisms for the formation ofradicals during the initiation step (Scheme 125).415 Twocomprehensive reviews on this topic published in 1982 and1983 are available.414,415
Other groups of high-valence metal catalysts are the metalchelates without additives.417 The polymerization of MMAproceeds in the presence of ammonium trichloracetate togetherwith copper acetylacetonate at 80 °C. The generation oftrichloromethyl radical was proposed to proceed via a SETmechanism (Scheme 126). Mn(1,1,1-trifluoroacetylacetonate)3
Scheme 121. Metal Complexes−Haloalkanes-InitiatedPolymerizations391
Scheme 122. Degenerative Iodine Transfer Mechanism
is also an effective initiator for radical polymerization of MMA.However, it is not effective in the polymerization of styrene.417b
The radical polymerization catalyzed by high-valence metalprior to 1995 is summarized in Table 5.
3.1.13. Termination of Radical Polymerization byFeCl3 and CuCl2 via SET Mechanism. Kochi observed thechain-termination by FeCl3 and CuCl2 in Kharasch additionreactions (Scheme 127).430 No polymerization process wasobserved no matter if the radicals were generated fromdiazonium salts or peroxides. Moreover, when I2 was usedeven in the presence of excess halide ion, only Ar−I wasisolated.430
Table 3. Summary of Metal0, Initiators, and Monomers Used in Metal-Catalyzed Radical Polymerization Prior to 1995a
b CCl4, poly(vinyl trichloroacetate) MMA 1964 388Mo(CNPh)6
b CCl4, poly(vinyl trichloroacetate) MMA 1965 392aW(CNPh)6
b CCl4, poly(vinyl trichloroacetate) MMA 1965 392aNiO2
b Sty 1965 403Ni(PPh3)4
b CCl4, poly(vinyl trichloroacetate) MMA 1966 393, 404Na3[C6H5CH2Co(CN)5]
b MMA, Sty, VAc, AN 1969 405VO(acac)2Cl, VO(8-quinolyloxyo)2OCH3
b MMA 1974, 1975 406Re2(CO)10, Mn2(CO)10, Os3(CO)12
c MMA, TFE 1975, 1976 407PtII(dimethyl-(2,2′-bipyridyl))c TFE 1976 408Mn(CO)5Cl,
cCH3Mn(CO)5,cCH3COMn(CO)5
c TFE, MMA 1976, 1978 409BzCr(CO)3
c and TolCr(CO)3 MMA, Sty 1977, 1984 410aX = Cl, Br, I. bThermally initiated. cPhotoinitiated. dReaction was carried out at 25 °C with inactive sodium light.
Scheme 124. Deactivation of Propagating Radical Chain byCuII
Scheme 125. Radical Formation by CuII Catalysis415
The termination of polymerization of AN, MAN, Sty, MA,MMA, and VAc catalyzed by AIBN in DMF was found to bemediated by FeCl3 (Scheme 128). In a comparison of the DP
of the polymer terminated by FeCl3 with the bimolecularterminated polymer, a SET mechanism was proposed toaccount for the termination.431 The rate of the termination forPS was faster than that of PAN and PMAN, supporting theSET mechanism proposed because PS radical is a betterelectron donor than PAN radical.431b An induction period wasobserved for the polymerization of Sty due to the large rate oftermination observed in DMF. For other monomers such asAN, MAN, MA, and MMA, the rate of polymerization in DMFis inversely proportional to FeCl3 concentration.431c Theproduction of Fe2+ was confirmed spectroscopically.432
The rate of termination of polymerization of Sty by FeCl3was compared to that of Fe(DMF)6
3+(BF4)3. FeIII compounds
without chloride anions showed a smaller rate constant for thetermination step than that of termination by FeCl3. Thus, Cl
−
ion showed an accelerating effect in the SET process betweenFeIII and the radical, presumably by bridging between twospecies.432
3.1.14. SET-Mediated Living Radical Polymerization.Titanium-mediated SET epoxide ring-opening living radicalpolymerization is discussed in section 3.2.5.1. This section willdiscuss briefly SET-LRP, SET-DTLRP, and a brief mechanisticdiscussion on ATRP.The application of SET processes to LRP led to the
discovery of SET-DTLRP in 2002 and of SET-LRP.8 During
concurrent investigations on the development of metal-basedcatalysts for use in sulfonyl halide initiated LRP, Cu and othermetal catalysts were tested for the LRP of vinyl chloride (VC).Until early 2001, the LRP of VC was not accessible, and it wasconsidered to be impossible via a metal-catalyzed process.433
Synthesis of poly(vinyl chloride) (PVC) by free-radicalpolymerization of vinyl chloride is not accompanied bybimolecular termination, and, therefore, the persistent radicaleffect is not accessible for the polymerization of VC. Instead,radical polymerization of VC is dominated by a high chain-transfer constant to monomer and polymer. Attempts topolymerize VC at temperatures higher than room temperaturewould result in an even higher rate of chain transfer. Even theCuIX/ligand complexes used for ATRP failed to reactivate therelatively inert ∼CHClX end groups, and it was suggested thatthe development of more powerful catalysts is needed for thepolymerization of monomers that form highly stable endgroups such as the case of VC. “Future catalysts may providesufficient reactivity for other monomers that cannot bepolymerized using current ATRP catalysts. For example, amonomer that would generate a more stable halogen endgroup, such as vinyl acetate (chloroacetoxy ethane), vinylchloride (dichloroalkane), or ethylene (chloroalkane), does notpolymerize using the current catalysts due to its low Keq.”
433
The year 2001 witnessed the investigation of metal-catalyzedradical polymerization of VC initiated with various activatedhalides in the presence of CuI, Cu0, Fe0, TiCp2Cl2, and othermetal catalysts in the presence of N-containing ligands.434 Inmost cases, the monomer conversions were <40% because ofthe formation of inactive species via chain transfer to PVC andother side reactions. However, significant propagation wasobserved only for zero-valence metals, as they were able toreinitiate from geminal dihalo or allylic chloride structures. Incontrast to CuI/ligand, Cu0/ligand showed remarkable activity.Cu0/ligand was able to catalyze the polymerization of VC withall active initiators tested, and most important it maintained allof the fundamental features of a LRP, such as a lineardependence of the molecular weight with conversion and adecrease of polydispersity with conversion. However, theextremely high chain-transfer constant of VC prevented theestablishment of the persistent radical effect that shifts theequilibrium of the polymerization toward dormant species by
Table 5. Summary of Initiators and Monomers Used in the Radical Polymerization by High-Valent Metal Complexes Used inRadical Polymerization Prior to 1995415
metal complexes initiator monomer year ref
trace of CuII present in the hydrophilicmacromolecules
increasing the concentration of CuIIX2 species by bimoleculartermination. The problem of formation of dormant species,which in turn results in living nature of the polymerization, wassolved by disproportionation, an unavoidable property of CuI/N-ligand in polar solvents, such as water, DMSO, DMF,alcohol, etc.121 For more details on disproportionation of CuI,section 2.2.1.2 must be consulted. Given the high Kdisp of Cu
IX(Table 1) concentration in a typical CuI-catalyzed polymer-ization in polar solvents like water, DMSO, DMF, MeOH, etc.,only a negligible amount of CuI is stable in the solution. Thedisproportionation of CuBr generates extremely reactivecatalyst Cu0 atoms, that depending on the ratio between therate of activation and nucleation, may also nucleate and formnanoparticles, and CuII, which maintains the living nature of thepolymerization by deactivating the growing radical chains.118,120
Thus, self-regulation of CuIIX2 deactivator and “nascent” Cu0
eliminates any need for either bimolecular termination orexternal addition of CuIIX2 (Scheme 129). This newly invented
LRP methodology was named “SET-DTLRP” because it isbased on the SET activation of C−X from initiator or dormantspecies via Cu0 surface and nascent atoms and SET deactivationwith CuII X2/ligand as well as by degenerative chain transfer(DT).137,434,435
SET-LRP evolved from SET-DTLRP, wherein the DTprocess has been observed under proper conditions to beslower than activation by the catalyst. In SET-LRP, initiation,activation, and deactivation proceed through a SET process(Scheme 129).8,121 Activation of alkyl halide initiator or thedormant species takes place via a SET process, which eventuallyresults in a reductive dehalogenation (Scheme 130). Dependingon the substrate and the nature of the leaving group, thissequence (SET and subsequent fragmentation) can beconcerted or stepwise.306,435 The reductive dehalogenationprocess for alkyl halides derived from acrylates, vinyl halides,and styrenes, and the initiators commonly used in SET-LRPwas studied by energy profile modeling.118 For the alkyl halideswith electron-withdrawing groups, such as the initiators used ina typical SET-LRP, the barrier for the activation step betweenstepwise and concerted dissociative SET is lower as comparedto relatively more electron-rich alkyl halides. This observationcan be attributed by the fact that the greater electron-withdrawing capacity of the alkyl halide substituent stabilizesthe radical−anion pair (R·δ+X−), which is generated from thehalide anion and the radical with partial positive charge densityinduced by its electron-withdrawing substituent. This in turnreduces the equilibrium bond length of the radical−ion pair,and accelerates the SET process.118
Recent studies have demonstrated the disproportionation ofCuBr in the presence of N-containing ligands, such as tris(2-amino)ethyl amine (TREN) and tris[2-(dimethylamino)ethyl]-amine (Me6-TREN) by UV−vis spectroscopy and visualizationof spontaneous generation of Cu0 nanoparticles and CuII/ligand in a diversity of solvents, such as polar aprotic (Figure 5),alcohols (Figure 6), and nonpolar solvents (Figure 7). Inaddition to these organic solvents, many monomers, both polarand nonpolar, such as acrylate, methacrylate, Sty, show instantdisproportionation of CuBr/ligand (Figure 8). In the case ofDMSO, an excellent solvent for SET, the nascent Cu0
generated by the disproportionation is rapidly consumedupon addition of 2-bromopropionate as compared to a slowerrate in toluene and other nonpolar solvents. This resultdemonstrates the dependence of SET activation on solventpolarity.134,437 The color of the solution indicated the solubilityof CuIIX2 in the solvent, while the precipitate showed theamount of Cu0 generated via disproportionation. In somesolvents, such as toluene (Figure 7), CuIX disproportionates.However, the CuIIX2 generated is not soluble as can be seenfrom the colorless toluene solution. The SET radical polymer-ization in toluene is not living due to the slow reaction rate ofthe heterogeneous deactivation of the propagating radicals withCuIIX2 solid.
438
In a recent study,439 it was demonstrated that the decantationof the reaction mixture from the catalyst, “nascent” Cu0
colloidal nanoparticles generated from the disproportionationof CuBr/ligand, during SET-LRP results in polymerizationbeing completely stopped (Figure 9). On the other hand, whenhydrazine activated Cu0 wire is used as catalyst and thepolymerization was interrupted by lifting the Cu0 wire wrappedaround the stirring bar out of the reaction medium with amagnet, the polymerization still proceeded, but at a muchslower rate. In the latter case, the presence of Cu0 colloidalparticles, generated from the disproportionation of CuBr/ligand, even after removal of Cu0 wire was attributed to thecontinued polymerization in the absence of the Cu0 wirecatalyst. This complete or partial interruption in the polymer-
Scheme 129. Mechanism of SET-LRPa
aReprinted with permission from ref 121. Copyright 2006 AmericanChemical Society.
Scheme 130. Contributing Reactions Involved in SET-LRPa
aReprinted with permission from ref 436. Copyright 2012 John Wiley& Sons.
ization process by separation of Cu0 catalyst and the reactionmixture explicitly demonstrates that the soluble CuBr/ligand isnot a major contributor; instead colloidal Cu0 particlesgenerated from the disproportionation of CuBr/ligand are thecatalytic species. The TEM micrographs of “nascent” Cu0
nanoparticles were also observed during the disproportionationof CuBr/ligand in DMSO. The “nascent” Cu0 particlesgenerated from the disproportionation of CuBr/ligandagglomerate into visible particles. Interestingly, upon additionof the methyl 2-bromopropionate initiator, these Cu0 particlesare consumed immediately with complete disappearance of theparticles.439
Thus, SET-LRP has emerged as a robust technique for livingradical polymerization, producing polymers with high chain-endfunctionality even at complete monomer conversion. The 100%chain-end functionality was analyzed by multiple techniques,such as characterization of the polymer chain end by NMR andMALDI-TOF before and after functionalization via thio-bromoclick chemistry, and chain extension experiments. Only thiscombination of analytical experiments corresponds to thatrequired to confirm the structure of new organic compoundsand therefore is sufficient to demonstrate the structure of thepolymer product and to compare different polymer productsresulted from different methods of living polymerization.440
However, nonpolar solvents such as toluene and hexane inwhich the solubility of CuII/ligand is extremely low, as observedfrom the lack of color even in the presence of the Cu0, resultedin disproportionation, and with solvents that do not promotedisproportionation of CuI/ligand, such as MeCN, the polymer-ization is nonliving.441 It is remarkable that SET-LRP providesaccess for the first time to ultrahigh molar mass polymers withnarrow polydispersity from both polar and nonpolar monomers
such as poly(MA) in DMSO (Mn = 1 400 000, Mw/Mn = 1.15,in 10 h),121 in MeOH (Mn = 800 000, Mw/Mn =1.15, <3 h),442
and poly(2-hydroxyethyl methacrylate)443 in DMSO (PHEMA,Mn = 1 017 900,Mw/Mn = 1.49, 38 h). Recently, a new group ofdisproportionationg solvents, that is, fluorinated alcohols, wasstudied by Percec437a,b,444 and other laboratories.445 It wasdemonstrated that an excellent SET-LRP can be achieved in2,2,2-trifluoroethanol (TFE) or 2,2,3,3-tetrafluoropropanol(TFP) between 23 and 50 °C for both hydrophobic andhydrophilic acrylates and methacrylates. A binary mixture ofthese solvents with DMSO allowed the synthesis of high molarmass polymers of hydrophobic acrylates, poly(nBA) with Mn =527 670,Mw/Mn = 1.21 in 12 h, and poly(EHA) withMn = 913101, Mw/Mn = 1.20 in 15 h via SET-LRP.444b In a recent study,Haddleton’s laboratory demonstrated that the CuII/Me6-TRENand “nascent” Cu0 generated by the extremely rapiddisproportionation of CuI/Me6-TREN in water result in anextremely fast SET-LRP producing polymers with excellentchain-end functionality and narrow molecular weight distribu-tion.446 Monteiro’s laboratory recently reported SET-LRP ofSty with the macrobicyclic ligand NH2capten. The SET processin this reaction was an OSET, because the encapsulation of themetal donor in the macrobicyclic ligand prevents the stronginteraction/bridging between donor and acceptor.447 Non-metal-mediated SET-LRPs were also reported.8 Sulfur-contain-ing groups such as sodium thiolate were demonstrated as goodSET donor as well as environmentally benign.259 The Na2S2O4-mediated LRP of VC initiated with CHI3 with the aid ofsuspension reagents was achieved.8 The progress of non-transition metal-mediated LRP was reviewed by Percec’slaboratory.8 In SET-LRP, none of the starting and finalmaterials including solvents, monomers, ligands, and polymers
Figure 5. Visual observation of Cu0 nanoparticles and CuBr2 generated from the disproportionation of CuBr in polar aprotic solvents in the presenceof Me6-TREN (a) and TREN (b). Conditions: solvent = 1.8 mL; [CuBr]/[N-ligand] = 1/1. Pictures were taken 10 min after mixing the reagents.134
Reproduced with permission from ref 134. Copyright 2013 The Royal Society of Chemistry.
must be purified, and the polymerization tolerates also oxygenfrom air because Cu0 is a well-known deoxygenation catalyst.Recent engineering comparisons of different metal-catalyzedliving radical polymerizations indicated that SET-LRP is the
only process with potential for commercial scale develop-
ments.448
3.1.14.1. Brief Mechanistic Discussion of ATRP. Atom-
transfer radical polymerization (ATRP)5,6,7b,375d has been
Figure 6. Visual observation of Cu0 nanoparticles and CuBr2 generated from the disproportionation of CuBr/Me6-TREN in a range of alcohols at 25°C. Conditions: solvent = 1.8 mL, [CuBr] = 16.5 mM, [CuBr]/[Me6-TREN] = 1/1. Pictures were taken 10 min after mixing the reagents.134
Reproduced with permission from ref 134. Copyright 2013 The Royal Society of Chemistry.
Figure 7. Visual observation of Cu0 nanoparticles generated from the disproportionation of CuBr/Me6-TREN in nonpolar solvents at 25 °C.Conditions: solvent = 1.8 mL, [CuBr] = 16.5 mM, [CuBr]/[Me6-TREN] = 1/1. Pictures were taken 15 min after mixing the reagents.134
Reproduced with permission from ref 134. Copyright 2013 The Royal Society of Chemistry.
proposed to proceed via a “concerted homolytic dissociation ofalkyl halides”5,449 (Scheme 131). A detailed mechanisticdiscussion would be too extensive in the context of thisReview. Therefore, only the activation of alkyl halides will bediscussed. In 1995,450 the CuI-catalyzed radical polymerization
of Sty using 1-phenylethyl chloride as initiator was reported andnamed “ATRP” according to the concept of AT defined byKochi (Scheme 131).61,62 Later, the same laboratory definedthe AT process as a “one-step dissociative electron transfer toform a radical and an anion”5 (Scheme 131), and claimed thatthis AT process is identical to ISET,449a,c,d most probablyaccording to the definition of Saveant (section 2.1.5).35
The activation/deactivation equilibrium between dormantspecies R−X and the propagating radicals was suggested to becomposed of the four elementary contributing reactions fromScheme 132. Therefore, theoretically the overall equilibrium
Figure 8. Visual observation of Cu0 nanoparticles generated from the disproportionation of CuBr/Me6-TREN in a range of commercial polarmonomers (a) and nonpolar monomers (b) at 25 °C. Conditions: monomer = 1.8 mL, [CuBr] = 16.5 mM, [CuBr]/[Me6-TREN] = 1/1. Pictureswere taken 15 min after mixing reagents, except DMA, which was taken 2 h after mixing the reagents.134 Reproduced with permission from ref 134.Copyright 2013 The Royal Society of Chemistry.
Figure 9. Interrupted SET-LRP demonstrating role of “nascent” Cu0. Reprinted with permission from ref 439. Copyright 2013 The Royal Society ofChemistry.
constant of ATRP must be a multiplicative addition of theequilibrium constants of the four steps from Scheme 132.
DFT calculations of bond dissociation energy of various alkylhalides including initiators, monomers, and dormant specieswere performed on the basis of the homolytic cleavage of theC−X bond to study the thermodynamics of ATRP.449a−c Whilethe bond strength of R−X and the reduction potential of CuI
play a role in activation, the division of these four contributingreactions is not relevant to the actual mechanism of reductivedehalogenation discussed in detail in sections 3.1.11−3.1.13,regardless if the process is ISET or OSET, and, therefore, theycannot account for the mechanism from Scheme 132. Even ifthe R−X cleaves in a homolytic fashion, which is notencountered in any ET-mediated reductive dehalogenationreactions (sections 3.1.11−3.1.13), the interaction between theD (CuI species) and A (R−X) must be incorporated.Therefore, these and other recent mechanistic studies indicatethat ATRP may follow the more traditional sequence ofreactions discussed in sections 2.1.2, 2.1.4, 3.1.11−3.1.13, ratherthan the one from Scheme 132.Recent studies using electrochemical methods investigated
the nature of CuI catalyst in ATRP (Scheme 133).451 It was
concluded that “[CuIL]+ is the only species reacting with RXeven in the presence of significant amounts of CuIX2
− and/orXCuIL”451a (X = Br, Cl; L = Me6TREN). “These findings posesome questions on the significance of the literature values ofKATRP and kact” because [CuIL]+ was not considered in any ofthe previous calculations.449c,451a
While the true catalyst for other CuIX-catalyzed organicreactions was not determined, the catalytic species shown inScheme 3 might hint to the true nature of CuI active species inother organic reactions.451a
3.2. Reactions Involving SET to Carbonyls, Olefins, andEpoxides
3.2.1. McMurry Reaction. After a series of preliminary dataon the preparation of alkene from pinacol and ketone,452 theJohn E. McMurry laboratory reported an efficient synthesis ofsymmetric alkene from reductive coupling of ketones andaldehydes with TiCl3/LiAlH4 (Scheme 134).453
Saturated and unsaturated aliphatic ketones and aldehydeswere coupled in good and excellent yields even in the case ofadamantylideneadamantane. Later, the reaction was found to be
not reproducible by numerous groups as well as by McMurry’sgroup. Modifications were made by replacing TiCl3 withactivated Ti metal produced by reducing TiCl3 with 3 equiv ofpotassium. Yields are good to excellent for aliphatic ketonesand aldehydes regardless of their steric hindrance. However, inthe case of aromatic ketones, the product was formed andsequentially reduced to tetraarylethanes. The over reductionwas solved by replacing potassium with Cu−Zn.454 Thereaction tolerates functional groups including acetals, saturatedalcohols, alkenes, alkyl silanes, amines, ethers, halides, vinylsilanes, and partially tolerates alkynes, amides, carboxylic acids,esters, nitriles, and toluenesulfonate. Unsaturated alcohols arecoupled, pinacols are reduced to alkenes, and other severalfunctional groups such as epoxides, enediones, halohydrins, α-haloketones, aromatic nitro groups, oximes, and sulfoxides arenot tolerated.455 One particular and important application ofMcMurry reaction is in the synthesis of cyclic alkenes. Anunusual and interesting characteristic of this reaction is thetolerance of steric hindrance (Scheme 135), indicating a radicalmechanism or carbeniod mechanism.
Reductive cross-coupling was achieved in good yields insome cases, and the intramolecular coupling was also achieved.A large diversity of strained cyclic alkenes was synthesized.However, because of the radical intermediates generated in thisreaction, the alkene formed consists of a mixture of cis andtrans products. Another restriction of this reaction is the limitedapplicability in coupling of asymmetric ketones or aldehydes.McMurry reviewed his reaction in 1989 with some recom-mendations to modified reaction conditions.455 However, evenwith the modified conditions, the synthesis with reproduciblehigh yields continues to require some practice with cyclo-hexanone. Poor quality reagents, solvents, and intrusion of airall cause inferior results.456 New titanium species were designedto overcome the shortage and better understand themechanism. Progress from 1989 to 1998 includes applyingcommercially available titanium powder for chemoselective
Scheme 132. Contributing Reactions of ATRP449d
Scheme 133. True Catalyst for ATRP451
Scheme 134. McMurry Reaction
Scheme 135. Structures Synthesized by McMurryReaction455
reactions,457 the development of TiCl4−Zn system, applicationof McMurry reaction conditions in pinacol coupling, and betterunderstanding of the mechanism.456 Coupling between ketonesand amides to synthesize substituted pyrrole and indolederivatives was also reported.456,458 Recent progress inMcMurry coupling is the selective cross-coupling betweenketones. By studying model substrates, it was observed that O-or N-containing groups decrease the reaction rate and promotecross-coupling reactions. Hence, a strategy to install a directinggroup with O or N and remove the group after McMurrycoupling to promote cross-coupling over homocoupling wasdeveloped.459 The method is limited to the scope of directinggroups and the synthetic methods to remove the directinggroups (Scheme 136).459
Fourteen tetraarylethenes were synthesized by this proto-col.460 The McMurry reaction was also applied to the synthesisof porphyrin-based dimers with fixed orientations. The reactionyield is strongly impacted by the quality of reagents, the natureof titanium reagent, and the presence of air.461 Microwave-assisted coupling was also reported.462
Initially, in situ generated TiII was considered as the activespecies. However, Ti0 was found to be the real catalyst asevidenced by no product formation when TiIICl2 was used.
454
Formation of both alkene isomers excludes a concertedmechanism. The failure in the reduction of trans-9,10-decalindiol indicates a five-membered ring is essential in theformation of the alkene product. The comparable yield ofalkene generated from cis and trans diols indicates that thereaction proceeds on Ti0 surface instead of soluble Ti0 species.The original mechanism of the McMurry reaction involves theSET transfer and radical-based deoxygenation. However,recently, a carbene intermediate mechanism was also proposed(Scheme 137).456 The similarity between titanium and tungstenled to a re-examination of the mechanism. Recent work thatemerged supports the carbenoid intermediate mechanism. X-ray photoelectron spectroscopy indicated that the nature ofactive Ti species is a mixture of Ti cations in +1, +2, and +3oxidation states instead of Ti0.463 A titanium hydride was alsoproposed to be the actual catalyst.464 More insight into themechanism was obtained when i-Pr2CO was used instead ofacetone. Besides the coupling product, 2,4-dimethylpent-2-enewas also formed. The corresponding titanium pinacoloate,Cl3TiOC
iPr2CiPr2OTiCl3, was found to be unstable and, upon
decomposition, generated TiCl3 and i-Pr2CO. These dataindicated that the McMurry reaction might follow twopathways. When the ketyl radical anion is not stericallyhindered, their coupling proceeds via radical species. Whensterically hindered ketones are involved, the carbenoidmechanism is more likely.3.2.1.1. McMurry Reaction in Polymer Synthesis. The
McMurry reaction has been applied to the synthesis of
conjugated polymers. Only 7 years after the first report ondeoxygenation coupling of ketones, the McMurry reaction wasapplied to the synthesis of poly(p-xylylidene)s (Scheme 138,a).465 The product was not characterized in detail because of itslow solubility. As the reaction conditions for the McMurryreaction improved, the synthesis process was also modifiedinvolving monomers bearing alkyl groups to improve the
solubility of the polymer. Modified McMurry couplingconditions were also used in the synthesis of conjugatedpolymers (Scheme 138, b).466 The polymerization was reportedto be complete in several minutes and was not stereospecific.The degree of polymerization determined by vapor pressureosmometry and 1H NMR was only 31.466 Another class ofconjugated polymers synthesized by McMurry coupling wassubstituted poly(ferrocenylenevinylene)s (Scheme 138, c).467
Two polymer fractions were obtained. The lower molecularweight fraction contains a large number of −OH groups,presumably from titanium pinacolate intermediates that failedto deoxygentate. The same chemistry was approached by adifferent group 2 years later with ferrocenyl aldehyde instead offerocenylmethyl ketone.468 Alkyl groups were introduced toincrease the solubility of resulting polymer. The polymer wasobtained in quantitative yields with molecular weight from3000 to 10 000. The Mw/Mn of the polymer ranged from 2.24to 2.48. Poly(triphenylaminevinylene) was also synthesized bythe McMurry reaction, but the degree of polymerization was
not reported.469 Other polymers obtained by McMurrypolymerization includes poly(thienylenevinylene)s and poly-(terthienylenevinylene)s with thioether side chains470 and alkylside chains,471 poly(4,4-diphenylene diphenylvinylene),472 andpoly(N-octylcarbazole ethylene). The poly(N-octylcarbazoleethylene) synthesized was in cis conformation and displays ahelical conformation in solution.473 Poly(naphthylene vinylene)was also synthesized by McMurry coupling assisted bymicrowave with weight-average molecular weight of approx-imately 65 000 and Mw/Mn close to 3.474
The McMurry reaction has also been applied is supra-molecular chemistry, in particular for the synthesis ofmacrocycles.475 A brief illustration of this chemistry is shownin Scheme 139. Giant conjugated macrocycles composed ofoligothiophenes with up to 180π frames were synthesized(Figure 10) in 2% yield for the largest ring and 32% yield forthe smallest ring.476
Scheme 139. Synthesis of Cyclic Compounds via McMurry Coupling475
Figure 10. Giant macrocycles synthesized by McMurry reaction. Reprinted with permission from ref 476. Copyright 2006 American ChemicalSociety.
3.2.2. Pinacol Coupling. The formation of pinacols fromthe coupling of two carbonyl groups is called pinacol couplingreaction (Scheme 140).
The reaction was first discovered in 1859 by WilhelmRudolph Fittig.477 In 1927, Gomberg and Bachmann reportedthe synthesis of a pinacol from a ketone and Mg/MgI2mixture.478 More than 100 years after the original discovery,the reaction conditions evolved. Until recent decades, greatdevelopments were achieved in both stoichiometric andcatalytic methods to control the stereoselectivity of thisreaction.479 Because of the importance of this reaction,numerous electron donors including the traditional Na, K, Li,Mg, and SmI2 have been applied for this reaction. Recently,great interest in stereospecific and metal-catalyzed pinacolcoupling attracted great attention because the pinacol moietycan serve as a synthetic motif. The development in stereo-selective pinacol coupling reaction was reviewed by Chatterjeeand Joshi in 2006.479a Terra and Macedo reviewed the progressin intermolecular pinacol cross-coupling reaction up to2012.479b The metal-catalyzed reductive umpolung reactionswere reviewed until the year 2013.480
The mechanism of pinacol coupling involves SET tocarbonyl group to generate a ketyl radical anion or metaloxirane. The two different pathways available for thedimerization of ketyl radicals lead to two different stereo-isomers. When the metal is bridging between two radicalanions, the dl product is formed. When a nonbridgedintermediate was involved, the meso product is formed (Scheme141).
Recent work on cross-pinacol coupling of two substrateshinted at another possible mechanism (Scheme 142). In thecase of transition metals as catalyst, the metal oxirane isgenerated for one carbonyl group selectively, and the cross-pinacol coupling product would be the major product.Bimetallic coupling can be explained in the last part of themechanistic scheme. One metal activates one carbonyl groupby SET, while the other metal or metal cation serves as a Lewisacid. Recently, the magnesium ketyl radical was directlyobserved in the gas phase by mass spectrometry.481 Thisprovided clear evidence for the involvement of the SETmechanism in pinacol coupling (Scheme 142).
Mahrwald’s laboratory reported the synthesis of 1,2-unsym-metrical diols by retropinacol/cross-pinacol coupling reactions(Scheme 143).482
This reaction was proposed to proceed by formation ofbenzophenone radical anions. However, the ESR experimentfailed to capture the benzophenone radical anion. TiIII signalwas observed by ESR as well as confirmed by single-crystalstructure of a reaction precipitation. Hence, the authorsconcluded that the reaction mechanism involves SET frompinacol to TiIV complex, generating benzophenone radicalanions and TiIII. The benzophenone radical anion is of shortlifetime, and hence could not be detected by ESR.482
Asymmetric pinacol coupling reactions of aromatic aldehydeswere also reported. Tetradentate bisoxazoline ligands from L-serine and β-DDB were synthesized for this purpose (Scheme144).483
3.2.3. Rearrangement to Distonic Radical IonsGenerated by SET. Distonic radical ions are species withspatial distinction between the radical and the charge.484 Thefirst demonstration of distonic radical ions was their directobservation in the gas phase in 1978 (Scheme 145).485
Distonic radical ions bear the reactivity of both radicals andcharges and are capable of generating molecular complexity.486
Scheme 140. Pinacol Coupling
Scheme 141. Mechanism of Pinacol Coupling and the Originof Diastereoselectivity
Distonic radical ions are also found in organic mixed valencecompounds. These compounds were used for studies of SET inorganic chemistry, and the field was reviewed in 2012.487
Hence, the topic of organic mixed-valence compounds will notbe discussed here. This section will be devoted to distonicradical ions generated via SET and to their applications inorganic syntheses.In this section, we will use “nC, mO” terms to describe a
distonic radical anion. The nC refers to the C bearing radicalwhile mO refers to the O bearing charge. Moreover, the n, mrefers to the bond distance between these two sites. Forexample, a ketyl radical anion is termed as 1C, 2O.One of the most commonly used distonic radical ions might
be the ketyl radical anion. It is commonly generated from SETto carbonyl groups.479b The generation and reactivity patternsof ketyl radical anions are discussed in previous sections.3.2.3.1. Distonic Radical Anions Formed from Solvated
Electrons. Another example is the distonic radical anionobtained from reduction of alkynes, which was used in thesynthesis of cyclic compounds with terminal alkenes by theStork laboratory (Scheme 146).94
Alkali metal in liquid ammonia that provides solvatedelectrons was applied as a SET donor. The reaction takesplace via formation of a radical anion by the SET process fromthe solvated electron (Scheme 147).94
The deficiency of this chemistry is the low control ofstoichiometry of solvated electrons in the Stork cyclization
reaction.94 A modification was subsequently made to use thenaphthalene radical anions as donors to improve the yield.488
3.2.3.2. Distonic Radical Anions Formed by SmI2. Distonicradical anions with larger spatial separation of the radical andcharge sites can be generated by SET. One example is the SmI2-promoted tandem radical cyclizations reported by Curran’slaboratory.489 The distonic ketyl radical anion showed thereactivity of a radical and constructed four rings in one step.The acetal was not stable and was deprotected in situ to forman enatiomerically pure, crystalline product in 57% yield aftertwo steps. The distonic radical anion can also react similarly toanions and form lactones.490 These two cases demonstrate thedistonic radical ions generated via SET are capable of beingused in the construction of complex structures with highstereoselectivity (Scheme 148).
3.2.3.3. Distonic Radical Anions Formed by Electro-chemical Methods. 1C, 6O distonic radical anions can alsobe generated via SET by electrochemistry methods. Thedistonic radical anion can participate in homocoupling as wellas react with acetone (Scheme 149).492
The ring-opening reaction of three- or four-membered ringsvia SET also generated distonic radical anions.493 These radicalanions can be produced electrochemically or by a SETdonor.494 The reactivity patterns are summarized in Scheme150.SET-mediated scission of endoperoxides and related
Distonic radical anions can also particitpate in cycloadditionreactions to form strained rings (Scheme 152).497
The SET-induced Cope cyclization proceeds also via distonicradical anion intermediates.29,498 The Cope cyclization reactionvia radical anions is exothermic. The rate-determining step isthe formation of the molecular radical anion (Scheme 153).
3.2.4. Jacobsen−Katsuki Epoxidation. In 1986, imme-diately after the discovery that CrIII complexes are effective forepoxidation of alkenes,499 Kochi and co-workers preparedMnIII(salen) analogues and proved that Mn analogue is moreeffective than Cr in epoxidation of alkenes using iodosylben-zene as a stoichiometric oxidant (Scheme 154).500
It was also reported that substituents on the salen ligandaffect the stereochemistry of the product. The reaction wasproposed to proceed by a radical mechanism with [OMnV(salen)]+ as reactive species and oxo-MnIV dimer astransient species. In 1990, Jacobsen501 and Katsuki502
independently reported the MnIII(salen) complex for asym-metric epoxidation of unactivated alkenes (Scheme 155). Bothgroups designed their catalyst based on Kochi’s original catalystbut with substituents on carbon 8 and ortho to phenoxide oncarbon 3 to induce chiral epoxidation.Jacobsen and co-workers introduced a t-Bu group on carbon
3 of Kochi’s original catalyst (Scheme 155) and maintainedPhIO as the external oxidant. The structures of Jacobsen andKatsuki cataysts are illustrated in Scheme 156.
Scheme 144. Asymmetric Pinacol Coupling of AromaticAldehydes483
Scheme 145. Open Ethylene Oxide Ion Observed in the GasPhase485
Scheme 146. Radical Cyclization through Distonic RadicalIon Intermediate94
Excellent ee was obtained for cyclic and cis alkenes (up to93%), but low ee (20%) was obtained for trans alkenes.Terminal alkenes give poor to moderate ee. Jacobsen proposedthe alkene approaches the catalytic center MnvO from thetop as illustrated in Scheme 157.In 1991, Jacobsen made a modification in the reaction
conditions and employed NaOCl in basic solution as theterminal oxidant. This greatly lowered the cost of the reactionand made it more practical to synthetic organic laboratories.503
The presence of bulky groups at carbon 3 position was alsoproven to be crucial for the stability and selectivity of thecatalyst because the stereoselectivity originates from the stericinteraction between the larger substituent of alkene and thebulky group at position 3. Jacobsen also claimed that if thestereoselectivity comes from the slide-on approach, then thestereoselectivity issue with trans-alkenes will never beresolved.504 The mechanistic source for asymmetric additionwas further studied.505 The reactivity of irreversible-formedintermediates and corresponding enantioselectivity refinementcomes from ligand dissymmetry in a chiral catalyst. This isconcluded as the reason for asymmetric epoxidation.Katsuki’s catalyst bears a structure similar to that of
Jacobsen’s catalyst. The catalyst slows the epoxidation ascompared to the original catalyst but increases the stereo-selectivity of the epoxidation. Moderate ee was obtained for Z-alkene, but for E-alkene, the ee was still low. The generation ofketones as side products indicates the radical nature of thereaction. Contradictory to Jacobsen’s hypothesis, Katsukiproposed that the alkene approaches the catalyst in a side-onapproach (Scheme 157).506 Further work by Katsuki’slaboratory studied the donor ligand effect in the asymmetricepoxidation.507 Py-N-oxide and 2-Me-ImH and DMF wereused as donor ligands. Donor ligands were found to increasethe yield of epoxides as well as the ee of the reaction. The resultwas interpreted. Donor ligands stabilize high oxidative stateMnV species and lower the energy of the transition state, hencelowering the energy barrier of the reaction, which leads toincreased yield. The enantioselectivity of the reaction wasimproved by running reaction at lower temperature.508
Generation of a metallaoxetane intermediate was alsoproposed.509 So far, three mechanistic pathways have beenelucidated (Scheme 158).In an attempt to understand the transient species in Mn-
catalyzed epoxidation, MnIII(salen) complexes were oxidized.OMnIV(salen), HO−MnIV(salen), and H2O−MnIII(salen+·)were prepared and compared by various spectroscopictechniques. OMnIV(salen) was found to be the most possibletransient specie. However, the OMnIV(salen) isolated wasnot capable of oxidizing olefins.510
Scheme 148. Reactivity Pattern of 1C, 4O Distonic Radical Ions489−491
Scheme 149. Reactivity Patterns of 1C, 6O Distonic RadicalAnions491,492
Scheme 150. Distonic Radical Anions Generated by Ring-Opening Reactions491,493,495
Scheme 151. Generation of Distonic Radical Anions fromScission of Endoperoxides and Related Functionalities491,496
The developments of the Jacobsen−Katsuki epoxidationprior to 2005 have been reviewed extensively.108,499,511 Also,the development of recoverable chiral salen complexes has beenreviewed up to 2010.512 Hence, no recent development on
recoverable catalyst will be covered. Recently, a strategy ofasymmetric counteranion directed enantioselective epoxidationof MnIII(salen) complexes was reported.513 Because thecounteranion in MnIII(salen) was reported to impact the
Scheme 152. Cycloadditions of Distonic Radical Anions491,497
Scheme 153. SET-Induced Cope Cyclization and the Reactivity of Distonic Radical Anions29,491,498
Scheme 154. Kochi Original MnIII(salen) Complex
Scheme 155. Jacobsen−Katsuki Epoxidation
Scheme 156. Structures of Jacobsen and Katsuki Catalysts
Scheme 157. Substrate Trajectory
Scheme 158. Mechanism of Jacobsen−Katsuki Epoxidation
reactivity of the catalyst by donating electrons to MnV reactiveintermdiate and stabilize the intermediate, it was proposed thata chiral, bulky phosphate anion will increase steric hindrance atthe Mn center and block some alkene approach pathway to leadto higher selectivity (Scheme 159). Indeed, the bulkyl
phosphate anion increased the conversion to over 99% andthe enantiomeric ratio to 97:3. Conjugated alkenes, terminalalkenes, and cis- and trans-alkenes in cyclic systems were allepoxidized with good to excellent yields and excellentselectivities (Scheme 160).
The epoxidation of olefins with Mn catalysts bearingnonsalen ligands was also reported in the literature. Twovariants are known, the Mn−porphyrin system514 and theMnIII−H2O2 system.515 The former will not be discussedbecause metal porphyrin complexes represent a specializedtopic that has been the subject of a recent review.514 While forepoxidation of olefins by H2O2, Feringa laboratory and othergroups studied the mechanism of the reaction.515,516 It wasconcluded that MnIII acted as base in this catalytic system todeprotonate H2O2. For a more comprehensive understandingof the mechanisms in Mn-catalyzed oxidation of alkenes withH2O2, the readers are referred to a review published in August2013.517
3.2.5. SET-Induced Epoxide Ring-Opening Reactions.Epoxides are strained rings that open under nucleophilic,
electrophilic, as well as radical conditions. In 1957, Hallsworthand Henbest reported the reduction of vicinal epoxycyclohex-anes with lithium-ethylamine.518 The product is an axial alcoholgenerated from the attack of solvated electrons at the less sterichindered side of the epoxide. The procedure was later appliedin the reduction of bicyclic epoxides.519 Later in 1963, Sabatinoand Gritter demonstrated the free radical-induced epoxide ring-opening with t-butyl peroxide. The extraction of α-hydrogen-induced epoxide ring-opening followed by the eliminationreactions generates α,β-unsaturated alcohol and ketone.520
Later, tri-n-butyltin hydride and calcium in ethylenediamine inmethanol were used in the reduction of epoxide by SET.97,521
The Birch-type radical-induced epoxide ring-opening issummarized in Scheme 161.
Recent advances in Birch-type reduction include the use ofactive manganese in complete regioselective synthesis of 2-hydroxy esters or amides from epoxide ring-opening of α,β-epoxy esters or amides. Improved yields were obtained ascompared to SmI2 reduction reported previously despite theelectronic properties of the substrates. Over 90% regioselectiv-ity was obtained due to the conjugation of the aromatic ring.522
Another important type of radical source is titanocene. In1988, Nugent and RajaBabu reported the first case oftitanocene-induced cyclization of epoxyolefins. Carbonylgroups were tolerated.523 The intermolecular version wassoon reported by the same group as well as the reduction anddeoxygenation of epoxides.524 The process has since beenextensively studied mechanistically and applied in organicsynthesis. Recently, the titanoceneIII/water system was appliedin the radical reduction of epoxides.525
The mechanistic study of titanocene-induced ring-opening ofepoxide was carried out with cyclic voltammetric, kinetic,computational, and synthetic methods.526 The titanocene wasfound to exist as a dimeric radical species in THF solution. Thereplacement of THF by epoxide was found to provide the lowenergy barrier. It was also shown by computational chemistrythat homolytic breakage of C−O bond at less substituted C ismore favored in energy (Scheme 162). This is because theeffect of steric interaction between the epoxide and thecyclopentadienyl ligands is larger than that of radical stability.The activation energy was computed as 7−10 kcal/mol, and fitswith the fact that the reaction proceeds at room temperaturereadily. The computed product regioselectivity is very close toexperimental data (<3% error).Recently, SET-induced ring-opening of epoxides has drawn
further interest.109,527 Since 2007, the regiodivergent epoxide
Scheme 159. Asymmetric Phosphate Anion with MnV(salen)Complex
Scheme 160. Epoxidation with Achiral PhosphateCooperation
opening was reported by Gansauer’s laboratory.528 Theregiodivergent opening of the epoxide came from a doubleasymmetric process (Scheme 163).529 Further, the idea of
regiodivergent method in enantioselective catalytic radicalcyclizations was reported. The enatioselectivity of the reactionis the result of the Beckwith−Houk model.530
Besides the progress in regiodivergent synthesis, theformation of allylic alcohols from suitable epoxides by amixed disproportionation mechanism was also reported.531
Other single electron sources for epoxide opening appliedrecently include visible-light-induced radical epoxide ring-opening532 and electrodes-induced radical epoxide ring-open-ing.533
3.2.5.1. SET-Induced Epoxide Ring-Opening RadicalPolymerization. Inspired by research on Ti-catalyzed SETepoxide ring-opening reactions, the Asandei laboratory appliedthe chemistry to LRP of Sty.534 The TiIII derivative acted bothas catalyst to ring open the epoxide as well as a persistentradical to reversibly terminate the growing chains, thusmediating the LRP process. TiIII was generated in situ. Themechanism of TiIII-catalyzed ring-opening LRP is depicted inScheme 164.The polymerization was carried out at temperatures from
110 to 40 °C, with decreased Mw/Mn when the temperaturedecreased. The Mn obtained was as high as 28 000 with Mw/Mnlower than 1.3. For polymerization carried out at 60 °C, theMw/Mn obtained was lower than 1.1 and Mn was around 15000.534 Other initiators used included halides and peroxides.535
Aldehydes were proposed to be the most robust initiator, leastimpacted by reaction conditions, while epoxides are moreaccessible as well as provide pathways to graft copolymers.Peroxides failed to maintain chain end functionality, and halidesare sensitive to reaction conditions.535
Different ligands were investigated, including bisketonates,scorpionates, alkoxides, and half-sandwich compounds.536
Cp2TiCl was demonstrated to be the most efficient catalyst.Other reaction conditions including the nature of thereductants, the epoxide/Ti ratio, and the Ti/Zn ratio werestudied. The best conditions found involved the addition ofmonomer to TiIII reduced with 2 equiv of nano Zn and 0.5equiv of epoxide with respect to Ti at 90 °C.537 The LRP wasalso initiated with a wide range of aldehydes: aromatic,aliphatic, electron-rich, as well as electron-deficient. ROP ofε-caprolactone was elaborated for the synthesis of polyesters at90 °C.538
3.3. Reactions Involving SET to Sulfones and OtherSulfur-Containing Compounds
3.3.1. Julia−Lythgoe Olefination. The synthesis of E-olefins from sulfones and aldehydes was first reported by thelaboratory of Marc Julia in 1973.95 The original report involvesthree steps and an amalgam as reducing reagent in the laststep.95 Five years later, Lynthgoe and co-workers applied theoriginal conditions to the synthesis of conjugated dienes andobserved that the double bonds formed were exclusivelytrans.539 They also investigated the origin of stereoselectivity inthe alkene formation in a follow-up report.540 If branches areadjacent to the benzoyloxy or the arylsulphonyl groups, theproducts generated were exclusively trans. Otherwise, the
Scheme 162. Mechanism of Titanocene-Induced EpoxideOpening
Scheme 163. Regiodivergent Epoxide Opening via ElectronTransfer529
Scheme 164. Mechanism of Ti-Catalyzed Expoxide Ring-Opening LRP534
stereoselectivity of the reaction decreases. The origins of thestereoselectivity were suspected to result from the formation ofless hindered, lower energy trans radical.540 In 1991, anotherchemist also named Julia, S. A. Julia, and Kocienski replaced thefirst two steps in the original Julia reaction with α-lithiolatedbenzothiazolyl-sulfones and developed the one-pot synthesis ofE-alkene.541 The formation of alkenes from α-lithiatedbenzothiazolyl-sulfones by the Smiles rearrangement is thencalled a modified Julia olefination reaction or Julia−Kocienskiolefination reaction (Scheme 165).541,542 The Smiles rearrange-ment does not involve a SET process, and therefore it will notbe discussed here.
The initial mechanism of Julia−Lythgoe olefination wasproposed and studied by Lythgoe and co-workers. Theelimination step starts from a SET to phenylsulphone groupand elimination of phenylsulphinate, followed by a second SETreaction to produce an anion. The anion rearranges to the Econformation to minimize steric hindrance and then eliminatesthe carboxylate group (Scheme 166).539,540 By this mechanism,all H’s of the resulting alkenes result from the original ketonesand aldehydes. However, with deuterium incorporation experi-ments, Keck and co-workers found deuterium incorporation inthe final alkene when CD3OD was used as the deuteriumsource. This result is in contradiction with the mechanismproposed by Lythgoe group. Hence, an alternative mechanismwas proposed to count for the deuterium incorporation.543 TheSET process was proposed to happen after the formation of E-alkene to the vinyl sulfone group. The vinyl radical then acceptsan electron from the SET donor and abstracts a proton fromthe solvent or proton donor (Scheme 166).Later, it was proposed that the reduction mechanism by Na/
Hg is different from that by SmI2/HMPA because differentresults were obtained under these two conditions.544 Also, itwas proposed that the reduction mechanisms for β-hydroxysulfones and β-benzoyloxy sulfones differ. After the formationof the radical anion, in the case of β-hydroxy sulfones, thesulfone group leaves, while benzoyloxy leaves in the case of β-benzoyloxy sulfones. Hence, the reduction of β-benzoyloxysulfones is much easier than the reduction of β-hydroxysulfones.544b A recent study with SmI2 as SET donor revealedthat the reaction proceeds via a combination of bothmechanisms. The rate of the elimination step of a series ofacyloxysulfone was compared. It was found that the conjugationon both acyl or sulfone groups increases the rate of elimination.The work concluded that the SET step to sulfone group orbenzoyl group is reversible. Therefore, the radical fragmenta-
tion is the rate-determining step for Julia−Lythgoe olefination.The most stable radical will form, followed by elimination.Since the first report of Julia−Lythgoe reaction,95 this
methodology became attractive for the construction of CCfrom CO groups. As compared to the Wittig reaction,formation of benzylsulfone tolerates steric hindrance. Quite anumber of natural products synthesis incorporated this reactionin their key step synthesis.545 Some progress on the reductioninvolves replacing Na/Hg with more environmentally friendlyreagents, such as SmI2/DMPU/MeOH,543 SmI2/HMPA,546
and Mg/MeOH.547 The SmI2-mediated Julia−Lythgoe olefina-tion reaction showed higher functional group tolerance becausethe reaction conditions are milder.544b
Besides progress on reductants, sulfoxide instead of sulfonehas recently been employed in Julia−Lythgoe olefination.548
Sulfoxides can be reduced by the sulfoxide−metal exchangechemistry as well as SmI2/HMPA, avoiding the application oftoxic mercury. Another problem with sulfones is that the acidityof the α-H is too strong in the presence of another electron-withdrawing group and the anion does not add to aldehydesand even less to ketones. Sulfone leaving groups solved thisproblem. 1,2-Di-, tri-, and tetra-substituted olefins weresynthesized in moderate to good yields with high stereo-selectivity on E products (Scheme 167).548
3.3.2. Sulfination and Sulfinatodehalogenation ofPerfluoroalkyl Halides. First reported in 1981,549 thesulfinatodehalogenation and sulfination reaction of perfluor-oalkyl halides have evolved into a very important class of radical
Scheme 165. Julia−Lythgoe Olefination and Modified JuliaOlefination
Scheme 166. Mechanism of Julia−Lythgoe OlefinationReaction
reactions of perfluoroalkyl halides. The reaction conditions aremild, nontoxic, nonexplosive, and environmentally benign.259
In their early work with potassium sulfite and perfluoroalkyliodide, Huang’s laboratory observed the transfer of iodo groupto sulfinate group in aqueous dioxane solution (Scheme168).549a,c,550
The replacement of I group with SO2K group in thedioxane/H2O mixture was not reported prior to this report.Because this reaction replaced one halogen group with sulfinatogroup, the reaction is termed sulfinatodehalogenation.It was further confirmed that light and the peroxides from
dioxane are essential to this reaction. When dioxane free ofperoxides was employed, no sulfinatodehalogenation wasobserved. No sulfinatodehalogenation reaction was observedin the dark as well. Free radical inhibitors such as hydroquinoneand p-dinitrobenzene stop the reaction. These results suggesteda radical pathway for the sulfinatodehalogenation reaction.549c
Later work by the same laboratory applied other sulfursources including sulfite,549c sodium dithionite,550 hydroxy-methane sulfinate,551 thiourea dioxide, and sodium bisulfite.552
The mechanism of sulfinatodehalogenation reaction wasstudied by the ESR spectra.553 The radical intermediate wastrapped with t-BuNO. The existence of perfluoroalkyl radicalwas confirmed by the ESR signal of t-butyl pefluoroalkylnitroxides radicals. The ESR experiments were also carried outto study the solvolysis process of sunfinatodehalogenationreagents. The radical anions SO2
−· and SO3−· were observed.
Hence, the mechanism of the initiation process was proposedas in Scheme 169. The sulfinatodehalogenation process isproven to be a radical chain reaction involving a SET process inthe generation of radical anions SO2
−· and SO3−· and
perfluoroalkyl radicals.552a,553
Wakselman’s laboratory observed the condensation ofbromotrifluoromethane with dithionite and with hydroxyme-
thanesulfinate salts in their study. The mechanism is consideredto involve the SET process described in Scheme 170.554
The reaction of polyfluorophenyl pentafluorobenzenesulfo-nates with sodium iodide was studied. Polyfluorodiphenylethers were generated as the main product when excess sodiumiodide was present (Scheme 171). When sodium iodide wasused as the limiting reagent, p-C6F5OC6F4SO3C6F5 was alsogenerated.555
The original sulfinatodehalogenation conditions apply toperfluoroalkyl iodide and bromide as well as polyfluorinatedcompounds such as CF2Br2, CF2I2, CF3CHClBr, and CF3CH2I(Scheme 172).259,277a However, the original sulfinatodehaloge-nation conditions do not apply to perfluoroalkyl chlorides.Modification of original sulfinatodehalogenation reactionconditions by using DMSO, a good solvent for SET, enabledthe sulfinatodehalogenation of perfluoroalkyl chlorides.556
When the reaction was carried out with Na2S2O4/NaHCO3in DMSO at 55−80 °C for 4−10 h, perfluoroalkyl chlorides,polyfluoroalkyl chlorides, even nonfluorinated compounds such
Scheme 167. Julia−Lythgoe Olefination of Sulfones548
Scheme 168. First Example of Sulfinatodehalogenation549
Scheme 169. Mechanism of Sulfinatodehalogenation
Scheme 170. Reaction of Bromotrifluoromethane withDithionite554
as chloroform react with alkenes to generate the additionproduct in 45−89% yields.556
Reaction with alkyne followed the same pattern, generatingan E/Z mixture of polyfluorinated alkenes (Scheme 173).556
DMSO was reported to be the best solvent because it favorsSET processes. Other solvents promoting SET processes suchas HMPA and DMF were also used, but hydrides were found asthe major product.556 The reaction is a SET-initiated radicalchain process. When an electron-transfer scavenger such as p-dinitrobenzene or a free radical inhibitor such as hydroquinonewas added, the conversion decreased. UV activation increasedreaction rate. Also, the radical process can be monitored by theformation of tetrahydrofuran derivatives (Scheme 174).556
The hydride source proposed in the original work wasDMSO.556 However, an isotope labeling experiment carried out
by a different group proposed that the hydride did not comefrom DMSO, the substrate, or water. NaHCO3 was proposed tobe the source of proton. Hence, a second SET to productradical followed by extraction of proton from NaHCO3 wasproposed.557
The sulfinatodehalogenation system has emerged as one ofthe most important reactions to introduce perfluoro orpolyfluoro groups in organic compounds.259 The additionand SRN1 reaction of perfluoroalkyl radicals has been discussedin previous sections. The sulfinatodehalogenation reaction wasreviewed up to year 2012.259,552a Therefore, only recentprogress after 2012 will be discussed. One recent advance isthe polyfuoroalkylation of pyrrole activated by sulfur dioxide(Scheme 175).558
Another recent development involves the use of sulfinato-dehalogenation conditions to elaborate the Na2S2O4-catalyzedliving radical polymerization of vinyl chloride and of acrylatesinitiated with iodoform.8,559 In water, SO2
−· dissociated fromNa2S2O4 serves as SET donor and initiates the polymerization.Moreover, SO2 generated from this reaction can add reversiblyto poly(vinyl chloride) radicals to provide transient dormantSO2
· radicals. More details are discussed in the SET-DTLRPsection.3.4. Reactions Involving SET to Arenes, Aryl Halides, andOther Conjugated Systems
3.4.1. Birch Reduction. In a pioneering publication in1937, Wooster and Godfrey560 showed that toluene could bereduced with sodium or potassium in liquid ammonia in thepresence of water. The reduction was indicated by thedisappearance of the blue color of alkali metal in liquidammonia. Interestingly, toluene did not participate in thereaction in the absence of water. This reaction was furtherdeveloped by Arthur J. Birch.92,561−565 In this reaction, solvatedelectrons are generated when alkali metals (Li, Na, K) aredissolved in liquid ammonia. The solvated electrons can giverise to 1,4-reduction of aromatic and heteroaromatic com-pounds, such as pyridines, pyrroles, and furans, to thecorresponding unconjugated cyclohexadienes and heterocyclesusually in the presence of an alcohol (Scheme 176).The mechanism of the Birch reduction was proposed by
Birch himself in his seminal publication because the generationof solvated electrons and metal cations by dissolving alkalimetals in liquid ammonia was already a known phenomenon.566
Solvated electrons are free electrons in solvated state in asolution and result in reduction of an acceptor by the OSETprocess. The Birch reduction involves two SET steps. The
Scheme 171. Mechanism of Iodide-Induced Synthesis ofPolyfluorodiphenyl Ethers555
Scheme 172. Activation of C−Cl Bond of Per- andPolyfluoroalkyl Halides in DMSO259,277a
Scheme 173. Addition of Perfluoroalkyl Chlorides toAlkynes by Sulfinatodehalogenation in DMSO556
Scheme 174. Trapping the Rf Radical as a TetrahydrofuranDerivative556
radical anion formed by addition of one electron to the reactingaromatic compound gets protonated by alcohol to generate aradical. This step is known to be rate limiting in the case ofbenzene.567 By rapid addition of a second electron, the radicalintermediate converts to a carbanion, which is followed by aprotonation, affording an unconjugated cyclohexadiene.Regioselectivity in Birch reduction depends upon theelectron-donating or -withdrawing nature of the substituents(Scheme 177). Electron-withdrawing groups stabilize the
negative charge by resonance effect and generate the orthoreduced product. The rate of the reaction decreases withincreasing electron-donating power of the substituents, and inthe case of heteroaromatic compounds at least one electron-withdrawing substituent needs to be present to get reducedunder Birch reduction condition. Unconjugated alkenes presentin the molecule are usually unaffected by Birch reduction.However, phenylated alkenes, conjugated alkenes with CCor CO, and internal alkynes can also be reduced under theseconditions.568,569
When an amine instead of ammonia is used in the presenceof Li or Ca, reduction of aromatic and olefinic compoundsresults in monounsaturated olefins, as well as the fully reducedproduct, which is known as the Benkeser reduction (Scheme178).570−572 The extent of reduction and selectivity in thisreaction can be controlled by varying the reaction conditions.
In the presence of an alkyl halide, the carbanion can alsoundergo nucleophilic substitution to result in an alkyl-substituted product.573,574 Alkylation of aromatic carboxylicacid by Birch reduction condition was first reported by Birch in1950 (Scheme 179).573
In 1969, Loewenthal and co-workers first demonstratedsingle step reductive alkylation of aromatic compounds(Scheme 180).575 Reductive alkylations of aromatic esters,amides, ketones, and nitriles typically are conducted in thepresence of 1 equiv of an alcohol.
The Birch reduction is one of the fundamental reactions inorganic synthesis due to its ability to regioselectively hydro-genate aromatic and heteroaromatic derivatives in addition toproduction of alkyl-substituted products. It has been used byseveral generations of synthetic organic chemists for theconversion of readily available aromatic compounds to alicyclicsynthetic intermediates.The application of Birch reduction in organic synthesis has
been reviewed thoroughly.576−578 The synthetic methodologyof Birch reduction followed by ozonolysis, introduced byBirch,17 is an efficient method to synthesize 1,3-dicarbonylcompounds (Scheme 181).579−581
In addition to the small molecular synthesis, Birch reductionprovides an excellent tool to synthesize robust reducedmacromolecular aromatic systems, such as graphane. In arecent development, it has been shown that the synthesis ofgraphane, partially hydrogenated graphene, can be accom-plished under Birch reduction conditions.582
3.4.2. Meerwein Arylation. In 1939, Hans Meerwein andhis co-workers reported the arylation of a substituted alkene byaryldiazonium halides in the presence of a metal salt catalyst,which was accompanied by loss of N2 (Scheme 183).
583 In thisseminal paper, Meerwein proposed the involvement of an aryl
Scheme 176. Mechanism of Birch Reduction
Scheme 177. Regioselectivity in Birch Reduction
Scheme 178. Benkeser Reduction
Scheme 179. Mechanism of Birch Alkylation
Scheme 180. Birch Alkylation
Scheme 181. Synthesis of 1,3-Dicarbonyl Compounds byBirch Reduction−Ozonolysis Methodology
cation as evolution of nitrogen has been observed (Scheme182).583
However, Kochi suggested that the formation of an arylradical is responsible for this reaction.584,585 He proposed thatwhen the reaction is carried out in the presence of CuIIX2, theactual catalyst is CuIX, which is generated in situ from CuIIX2and acetone (used as solvent for this reaction). The proposedmechanism involves two SET processes. In the first, SETproceeds from CuIX catalyst to aryldiazonium halide, followedby a subsequent N2 removal results in the formation of thehighly active aryl radical, which adds to the vinyl group toproduce the most resonance, stabilized radical intermediate.This is followed by another SET process and a deprotonatingstep to result in the arylated product of the alkene (Scheme183).
By trapping the alkyl radical generated upon the addition tothe olefin, introduction of other atoms and functional groups atthe place of the original halogen can be achieved. Reactionswith activated olefins, such as acrylates, acrylonitriles, vinyl-ketones, styrenes, and butadienes, are explicitly favored by thefast addition of the aryl radical to the olefin.586 Nonactivatedolefins, 1-alkenes, allylic alcohols, and amines as well as allylichalides,586 in contrast, result in a much slower addition reaction(Scheme 184).Under the original protocol, the Meerwein arylation reaction
was limited to alkenes with electron-withdrawing groups suchas in coumarin, cinnamic acid, and acrylic acid.586 Thislimitation was overcome by replacing the copper catalyst withstronger reducing agents, such as TiCl3 or FeSO4, whichexpanded the scope of Meerwein arylation to include evenelectron-rich olefins (Scheme 185).587
Another significant advancement587a,588 in this field is thephoto-catalyzed Meerwein arylation in which an aryl radical isgenerated by a SET process followed by denitrogenation uponits photolysis in the presence of a photoredox catalyst, such aseosin Y and [Ru(bpy)3]
2+ (Scheme 186).587a It is noteworthythat following the same reaction strategy, photocatalyzed
Pschorr reaction, which also involves SET from a photoredoxcatalyst, such as [Ru(bpy)3]
2+ upon photolysis, gives rise toexcellent yields of intramolecular cyclization reaction.589,590
Meerwein arylation provides a simple methodology for C−Cbond formation in organic synthesis. Excellent reviews areavailable including one reported in 2013.587a,591−594
3.4.3. Iodine-Based SET Oxidation. In the last twodecades, the family of hypervalent iodine reagents, both IIII andIV have emerged as efficient organic oxidizing agents viaSET.595−599 In 1991, Yasuyuki Kita600 showed that thehypervalent iodine reagent (IIII) can induce nucleophilicsubstitution toward electron-rich aromatic rings, such as phenylethers via a SET mechanism affording the corresponding radicalcation. Subsequently, in the presence of nucleophiles, oxidativearomatic substitution is accomplished as a result of the couplingof the formed radical cation and the nucleophile (Scheme 187).Kita599 claimed that this was the first report on hypervalent
Scheme 182. Meerwein Arylation Reaction583
Scheme 183. Mechanism of Meerwein Arylation584,585
Scheme 184. Meerwein Arylation of Activated andNonactivated Olefins586
iodine oxidation of aromatic compounds involving a SETmechanism.
Hypervalent iodine (IIII) reagents are well-known forphenolic oxidation processes under mild reaction conditions.It has been proposed that this reaction proceeds by a two-electron-transfer processes.599 In this reaction, the first step isthe ligand exchange of substrate at the iodine center thatsubsequently undergoes reductive elimination to generatenucleophile-substituted product along with the iodoarenecoproduct (Scheme 188).
However, Kita and co-workers showed that by using ahypervalent iodineIII reagent, such as phenyliodineIIIbis-(trifluoroacetate) (PIFA), in highly polar, but non nucleophilicfluoroalcohol solvents, such as 1,1,1,3,3,3-hexafluoro-2-prop-anol (HFIP) or 2,2,2-trifluoroethanol (TFE), direct nucleo-philic substitution of p-substituted phenyl ethers by a largevariety of nucleophiles was accomplished (Scheme 189). By
various experimental techniques, such as UV and ESR, as wellas trapping the intermediate radical cation, it was demonstratedthat the reaction proceeds by a SET mechanism (Scheme189).599
Following this strategy, the substitution reaction of phenylethers with various nucleophiles, such as azide, acetate,thiophenolate, thiocyanate, and β-dicarbonyl compounds, wasaccomplished. On the basis of this discovery, hypervalent iodinecompounds (iodanes) have rapidly emerged as a noveltechnology in organic synthesis for producing mixed biarylsfrom nonfunctionalized aromatic compounds by a metal freecross-coupling process.601−604 It is noteworthy that these IIII
complexes have reactivities similar to some toxic heavy metal-based oxidants including PbIV, HgII, CdIV, and ThIII-basedoxidants.601 Hence, the ability of hypervalent iodine reagents toundergo a SET process, in addition to their low toxicity,availability, and ease of handling, makes them promisingalternatives to the heavy metal oxidants.Kita’s laboratory has further modified the method of
nucleophilic substitution reaction by hypervalent iodinereagents, which was originally applicable for phenyl ethers toextend the scope of the reaction for a much broader range ofsubstrates in organic synthesis. The strategies used to generatearomatic radical cations with hypervalent iodineIII reagents canbe devised by two different methods: (a) use of thefluoroalcohol solvents, such as HFIP and TFE, due to theirhigh ionizing power combined with low nucleophilicity, whichwould effectively stabilize the in situ generated reactivearomatic radical cation species, and (b) by addition of theappropriate Lewis acids, which by coordination with iodineatoms enhances the SET oxidizing ability of the hypervalentiodine reagents toward aromatic compounds (Scheme 190).Using these strategies, a variety of useful oxidation reactionsusing hypervalent iodine reagents have been developed for botharomatic and heteroaromatic systems, such as thiophenes,
Scheme 187. Nucleophilic Substitution by HypervalentIodine Reagent (IIII)
Scheme 188. Mechanism of Phenolic Oxidation byHypervalent Iodine Reagent (IIII)
Scheme 189. Mechanism of SET Oxidation by HypervalentIodine Reagent (IIII)599
Scheme 190. Reaction Mechanism of SET by HypervalentIodine Reagent in the Presence of a Lewis Acid605
pyrroles, and indoles, in addition to the total synthesis ofnatural products (Scheme 190).605
In addition to the IIII reagents, 2-iodoxybenzoic acid (IBX),the precursor of Dess−Martin periodinane (DMP), is anotherhypervalent iodine reagent (IV) that involves a SET mechanismto substitute toxic metallic oxidizing agents (Scheme 191). IBX
was discovered by Hartmann and Meyer in 1893.606 However,due to its insolubility in most organic solvents and water, IBXdid not gain much attention in organic synthesis. However, in1994 Frigerio and Santagostino607 reported that IBX could alsobe used in the oxidation of alcohols instead of DMP. Sincethen, application of IBX and its analogues in organic synthesisincreased dramatically.However, it was only in 2001 that Nicolaou, Baran, and co-
workers reported that the mechanism of oxidation by IBXinvolves a SET process (Scheme 192).608
In a series of publications,609−612 Nicolaou and Baran havedemonstrated the diverse utility of IBX in organic synthesis.Organic synthesis of α,β-unsaturated derivatives of a range ofalcohols, ketones, and aldehydes systems from saturatedalcohols and carbonyl compounds, the selective oxidation ofthe benzylic carbon, the oxidative cyclization of anilides andrelated compounds, and the synthesis of amino sugars, etc.,were accomplished by using this nontoxic and readily availableorganic IV-based reagent.613,614 Moreover, by adjusting thestoichiometry of IBX, temperature, and time scale of thereaction, varying degrees of unsaturation could be achieved.612
In a review by V. V. Zhdankin, various analogues of IBX-basedSET oxidant reagents have been summarized (Scheme 193).613
Recent application of IBX was also reviewed.614
In a recent publication, Asandei’s laboratory615 demonstratedvia a photoinduced SET mechanism that a series of hypervalentiodides (IIII and IV), stable at room temperature, act as
protected synthetic equivalents of their expensive and hazard-ous or inaccessible peroxide or azo derivatives. The authorsdemondstrated that these hypervalent iodides have excellentability to act as least expensive and most convenient precursorsof CX3C
· and CX3I for radical (trifluoro)-(iodo)methylations,initiation of trifluoromethylation-based LRP, and in situoxidation of I2, CF3−I.
615
3.4.4. Sandmeyer Reaction. The Sandmeyer reaction wasfirst reported in 1884 by Traugott Sandmeyer12,616 when anattempt to prepare phenylacetylene by reacting benzenediazo-nium chloride with CuI acetylide produced chlorobenzene asthe major product without any trace of the desired compound.It was further revealed that CuI, which was generated in situ,catalyzes the reaction. A chlorine atom replaces the diazoniumgroup sequentially.12 He proposed that the reaction proceededin two steps via the formation of a complex between CuIX saltand aryldiazonium compounds (Scheme 194).12,616
Based upon this discovery, the nucleophilic substitutionreaction of aryldiazonium compounds by various CuI salts hasbecome a well-established field in organic synthesis (Scheme195). The nucleophiles include halides and pseudohalides, suchas halide anions, cyanide, thiols, water, and others.158,159,617−621
In 1942, W. A. Waters622 and later in 1957, J. K. Kochi157
proposed that this radical reaction proceeds via the formationof an aryl radical by a SET process from CuI catalyst toaryldiazonium salt followed by a ligand transfer from the CuII
salt (Scheme 196).The counteranion of the CuI salt has to match the conjugate
base of the aryldiazonium salt; otherwise a mixture of productscontaining both substituents is obtained. However, thesynthesis of aryl iodide can be accomplished by using KIwithout any need of catalyst. Nevertheless, the arylfluoride canbe synthesized by a modified method, known as the Balz−Schiemann reaction,623,624 where aryldiazonium tetrafluorobo-rates thermally decompose to aryl fluorides (Scheme 197).When aryldiazonium salt is heated with trifluoroacetic acid,
aqueous sulfuric acid, or with an aqueous solution of CuI salts,phenol is obtained as a final product.625 This reaction is calledSandmeyer hydroxylation.625 Sandmeyer reaction is one of thefundamental reactions in everyday organic synthesis to preparesubstituted aromatic compounds. Major advantages of thisreaction are its tolerance for both electron-donating andelectron-withdrawing groups in the aryl moiety and a simplemethodology, which allows the synthesis without the require-ment of purification of aryldiazonium salts after theirpreparation from aryl amines.626 However, classic Sandmeyerreaction requires addition of an excess amount of CuI catalyst.In this context, a recent advancement of the Sandmeyerreaction is the excellent yield in synthesis of aryl nitrile orthiocyanate by using only catalytic amount of CuI salts in thepresence of KCN and KSCN, respectively.627,628 In addition tothat, bromination of aryldiazonium compounds in the presenceof phenanthroline as a bidentate ligand and the phase-transfercatalyst dibenzo-18-crown-6 with a catalytic amount of amixture of CuI/CuII salts provides an almost quantitative yieldthat is a noteworthy progress (Scheme 198).629
3.4.5. SRN1 Reaction. The SRN1 (radical nucleophilicsubstitution, unimolecular) mechanism was first proposed in1966 independently by N. Kornblum’s laboratory630 and G. A.Russel and co-workers631 for activated alkyl and aryl halides,and in 1970 by Bunnet and Kim632 for unactivated aryl halides.They proposed that this reaction takes place by a chain reactionmechanism. In SRN1 the nucleophilic substitution is achieved
with aliphatic or aromatic compounds through a SET initiation,which generates a radical anion intermediate (Scheme 199,i).100,109,283,633,634
Fragmentation of the radical anion generated in the initiationstep is a crucial step in the SRN1 reaction. Various groupsproposed that the fragmentation of the radical anion (Scheme199, ii) is the rate-determining step for SRN1 reaction of manyalkyl halides with a series of nucleophiles.635 In addition, SET(Scheme 199, iv) from the radical anion generated by couplingof this radical with a nucleophile (Scheme 199, iii) in thepropagation cycle is also an important step, which determinesthe overall yield of the reaction. When the rate of any of thesesteps is not efficient, the chain reaction of the substitution willbe short or terminated. For instance, it is proposed that NO2
−
and CN− ions are not good nucleophiles in photolyticsubstitution reaction with an aryl halide, because they form astable radical anion by the resonance with an aryl radical(Scheme 199, iii); hence the chain propagation step isterminated due to lack of the following SET.636 Three differentpathways for the termination step have been shown in Scheme199. In addition, the fragmentation of the radical anion of thesubstitution product into an unreactive radical is anotherpossible termination pathway. Nucleophilic substitution re-action by SRN1 mechanism is a favored pathway for aromatic
Scheme 193. Chemical Structures of IBX Derivativesa
aAdapted from ref 613.
Scheme 194. Mechanism of the Sandmeyer ReactionProposed by Sandmeyer12
Scheme 195. Sandmeyer Reaction
Scheme 196. Mechanism of the Sandmeyer ReactionProposed by Waters and Kochi157,622
and aliphatic compounds when they are unreactive or showlimited reactivity through the polar nucleophilic mechanism,that is, SN1 and SN2 for aliphatic substrates, and through SNArand benzyne mechanism for aromatic substrates. Unactivatedaromatics, heteroaromatics, and vinyl halides are commonlyfound to undergo SRN1 instead of SNAr pathway. On the otherhand, aliphatic halides bearing electron-withdrawing groups,such as NO2, CN, CF3, perfluoroalkyl halides, and forsubstrates for which SN1 or SN2 is not feasible because ofsteric and strain factors (such as neopentyl halide, cycloalkylhalides), SRN1 is predominant (Scheme 200).637,638
Halides are most commonly used as a leaving group.However, many other leaving groups, such as RS (R = Ar,alkyl), ArSO, ArSO2, PhSe, Ph2S
+, RSN2 (R = t-Bu, Ph), N2BF4,R3N
+, N2+, N3, NO2, and XHg, are also used in SRN1 reaction
(Scheme 201).
Various methods can be applied for the initiation step inwhich SET occurs to the substrate, such as thermal orspontaneous SET, electrochemically,37 or photolytically.639 Inaddition, reductions of substrates via SET by solvated electrons,such as sodium amalgam in liquid ammonia, and SET frominorganic reagents, such as Fe2+, SmI2, are also widely used forthe initiation of the SRN1 reaction. Spontaneous or thermal SET
initiation can occur when an easily oxidizable ion is used as anucleophile. However, the rate can be further accelerated bylight. Photoinduced SRN1 is widely used for both aromatic andaliphatic substrates,639 and depending upon the reactionconditions, the SET process can take place by differentmechanisms, such as from a photolytically excited chargetransfer complex formed between Nu− and substrate, uponphotoexcitation of the nucleophile or with the help of asensitizer. Various aspects of the mechanism of SRN1 reactionand its application in organic synthesiss640 have been reviewedby various authors, most notably by Rossi.100,283,633,634
3.4.5.1. Polymerization via SRN1 Reaction. The involvementof SRN1 mechanism in the oxidation of 4-aryloxyphenols wasnoticed in 1962 by Price.641 Later the SRN1 character during thesynthesis of polyphenyl ether (PPE) was noticed by White andHeitz laboratory.156 The chain reaction was initiated by one-electron oxidation of the phenolate (Scheme 202).The SRN1-mediated synthesis of PPE prior to 1986 was
discussed by Heitz.642 Progress after 1986 includes the phase-transfer-catalyzed (PTC) polymerization of 4-bromo-2,6-dimethylphenol.643 The SET process was demonstrated to beresponsible for the polycondensation of 4-bromo-2,6-dimethyl-phenol under PTC conditions (Scheme 203).In aqueous phase, the phenolate forms a strong ion pair with
the ammonium cation. In organic phase, the onium phenolatesare unsolvated ion pairs with reduced cation−anion interactionand are very easily oxidized by the trace of oxygen from airdissolved in the reaction mixture. Oxygen from air wasdemonstrated to initiate the reaction. The PTC transfers theonium phenolates in the organic phase where it becomesextremely reactive due to lack of solvation. The PTC alsotransfers the onium hydroxide from the water phase to theorganic phase to deprotonate the phenol chain ends at highconversion and keep the propagation process active eventhough the concentration of BDMP is low.643 The chain-termination step in PTC synthesis of PPE was found to bereversible. The polymerization was found to be neither step-growth nor chain-growth but a “reactive intermediatepolycondensation” type.643−645 The copolymerization ofBDMP with 2,4,6-trimethylphenol (TMP), 4-tert-butyl-2,6-dimethylphenol (TBDMP), and 4-substituted-2,6-di-tert-butyl-
Scheme 200. Mechanism of SRN1 Reaction of AliphaticHalide637,638
Scheme 201. Substitution of Nitro Group withPhenylthiolate via SRN1 Mechanism
Scheme 202. SRN1 Mechanism in the Synthesis of PPE156
phenol was carried out.645 Both TMP and TBDMP were onlyincorporated as chain-end.645 The steric hindered 4-substituted-2,6-di-tert-butylphenols terminate the propagating chain end.4-substituted-2,6-di-tert-butylphenol A bifunctional initiatingphenol, 2,2-bis(4-hydroxy-3,5-dimethylphenyl)propane(BHDMP), was also used to synthesize telechelic PPE withtwo phenol chain ends.645
Besides PPE, another important type of polymer is alsoobtained via SRN1 mechanism. Heitz demonstrated in thesynthesis of polyphenyl sulfide (PPS) that the reactivity trendof halide is I > Br > Cl > F.646 Moreover, at low conversion,moderate (2000 g/mol) molecular mass polymers wereobtained. The molecular cations of PPS oligomer up to 8repeating units are stable in MS studies. Disulfide was formedin reaction.646 All of these behaviors cannot be explained bySNAr mechanism. Heitz proposed a SRN1 mechanism to explainthe behavior of the polymerization (Scheme 204).However, Lovell proposed a different mechanism to account
for the radical character in metal-catalyzed PPS synthesis.647
Cyclic voltammetry (CV) experiments demonstrated the
copper 4-bromobenzene thiolate undergoes one-electronoxidation easily. ESR spectroscopy indicates the existence oforganic free radical species throughout the polymerizationprocess as well as the formation of CuII in reaction.647a On thebasis of this evidence, a different mechanism involving a radicalanion process was proposed (Scheme 205).SRN1 mechanism was also reported to account for polymer-
ization and dehalogenation in the polyetherification of bis(arylchlorides) activated by carbonyl and sulfone groups withphenolates (Scheme 206).648
It was observed in the polyetherification of 4,4′-dichlor-obenzophenone (DCB) with tert-butylhydroquinone (TBH)that high molecular weight polymer was not obtained after longreaction time. Careful examination of the chain end by NMRrevealed that the termination by dehalogenation was the reasonfor low molecular polymers obtained when aryl chlorides wereused.648
Later, the polymerization of dihalophenylsulfones wasstudied.649 The polymerization showed that two mechanisms,the SNAr mechanism and the SRN1 mechanism, can compete
Scheme 203. Proposed Mechanism for PTC of 4-Bromo-2,6-dimethylphenol643
with each other depending if the phenolate involved is a strongor a weak electron donor and if the halide from the aryl halideis a good leaving group for a particular mechanism (Scheme207). The reaction rate for SNAr mechanism follows F > Cl >Br > I, while for SRN1, the trend is I > Br > Cl > F. The SRN1 isthe mechanism that counts for dehalogenation process of thepolymerization. Moreover, for aryl fluorides, no dehalogenationwas detected. For aryl iodides, the polymerization proceeded
exclusively via SRN1 mechanism. For aryl chlorides andbromides, two mechanisms proceed at the same time (Scheme207).In the polyetherification of aryl iodides, in the presence of
nitrobenzene, only oligomers were obtained, confirming aradical mechanism. However, heating aryl iodides withoutphenolate did not produce the dehalogenated product; hence,the radical was generated from the SET pathway.649
Scheme 204. SRN1 Mechanism Proposed by Heitz for PPS Synthesis646
Scheme 205. SRN1 Mechanism for PPS Synthesis Proposed by Lovell647
The properties of phenolates were also studied. Phenolateswith better electron-donating properties are better electrondonors and promote SET pathway, while phenolates withoutconjugation prefer SNAr pathway.
650
Finally, with the understanding of the reaction mechanism,high molecular weight polymers were synthesized without thedehalogenation process (Scheme 208).651
By increasing the nucleophilicity and reducing the electron-donating property of the phenolate, a nonconjugated phenolateled to high molecular weight poly(ether ketone)s with suitablebis-aryl chlorides. Moreover, adding another ketone spacerincreased the electrophilicity of the aryl chlorides and alsoresulted in high molecular weight poly(ether ketone)s from bis-aryl chlorides electrophiles.A recent advancement in the field of SRN1 was reported by
Studer and co-workers652 for the synthesis of polyarenes, suchas poly(p-phenylene) and polynaphthalene via SRN1 mecha-nism. This process does not require any transition metal, butrepresents an intriguing, novel method leading to π-conjugatedpolymers. The group demonstrated that an aryl compound,containing a Grignard reagent substituent (magnesiumchloride) and an anionic leaving group, readily polymerizes inthe presence of 2,2,6,6-tetramethylpiperidine-N-oxyl radical(TEMPO) at room temperature to yield poly(m-phenylene)with Mn of 3400−13 700, Mw/Mn of 1.60−2.20. It wasproposed that aryl Grignard (Ar−MgX) reagents undergohighly efficient homocoupling to biaryls by oxidation with the2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO) viaradical anion formation (Scheme 209), which upon fragmenta-tion of the leaving group gives an aryl radical.
This reactive radical subsequently adds to the anionicmonomer to give the corresponding radical anion (Scheme210).652
Further elimination of the leaving group from the coupledintermediate generates the chain-extended aryl radical, whichacts as initiator for the polymerization reaction. Interestingly,the initiation step can also be achieved by traces of air and doesnot require any transition metal. Most importantly, unlikeanionic chain growth polymerizations, strict exclusion ofmoisture is not necessary to run these reactions. The processhas been applied to the preparation of poly(m-phenylenes),poly(p-phenylenes), and a polynaphthalene, documentingexcellent potential of the SRN1 polymerization technique.
3.4.5.2. Persulfurated Aromatic Compounds. MacNicoland co-workers reported the synthesis of persulfurated aromaticcompounds from perfluorinated naphthalene in 1983. The twocompounds synthesized are listed in Scheme 211.653
Lather, in 1988, an unexpected reactivity of perfluoroalkanewas reported (Scheme 212).654 The mechanism was notScheme 209. Initiation by Oxidative Coupling of
understood. The authors corresponded the reaction mechanismto decomposing of perfluoroalkane by Na/NH3. A SETprocessed was proposed to account for the sulfuration process.Not many mechanistic studies were carried out. However,
some evidence showed support for the SET mechanism.Difficulties were encountered when p-nitrophenyl sulfide wasused. Considering p-nitrobenzene is a radical trap, this difficultyin incorporating p-nitro-substituted phenyl sulfide in thereaction might support the radical mechanism.655 Moreover,the dependence of the ratio of a byproduct on light conditionsalso supports the radical mechanism of the reaction.656 Theredox properties of the several polythioarene derivatives werestudied. It was found that polythioarene derivatives form radicalanion readily and are good electron acceptors.657 Later,polysulfurated branched molecules,658 molecular wires,659 aswell as molecular asterisks (star-shaped nanomoleculescontaining oligo(p-phenylene sulfide)s attached to a persulfu-rated coronene, benzene, or other multifunctional core)660
were synthesized (Scheme 213).Gingras reviewed molecular asterisks prepared from oligo(p-
phenyl sulfide)s and the persulfurated aromatic compoundsuntil the year 2006.655,661 The persulfurated coronene asteriskwas found to self-assemble into columnar structures.662
Another new direction for persulfuration chemistry is theincorporation of sulfur in multivalent glycodendrimers.663
3.4.6. Ullmann Reactions. The original Ullmann reactionwas reported in 1904 by Fritz Ullmann.664,665 He demonstratedthe coupling of two halogenated aromatic compounds to form abiaryl compound in the presence of stoichiometric amount ofCu0 powder in sand at 210−220 °C (Scheme 214). TheUllmann condensation or Ullmann ether synthesis is adevelopment of the Ullmann reaction in which a phenol iscoupled to an aryl halide to create a diaryl ether in the presenceof a copper catalyst (Scheme 214). A few years later, in 1906Iram Goldberg reported another modified Ullmann synthesis,that is, the formation of an biarylamine by reacting an arylhalide with an arylamine using CuI as catalyst in the presence ofK2CO3 as base.666 This reaction is known as the Ullmann−
Goldberg reaction. Currently, all of these reactions are calledUllmann-type reactions. The Ullmann coupling reaction will bediscussed in separate sections together with Ullmann ethersynthesis and Ullmann−Goldberg reaction.In all of these reactions, the order of reactivity of the aryl
halide is I > Br > Cl, whereas aromatic fluorides are completelysilent.667,668 Milder reaction conditions can be used when Ni0
complexes are used instead of Cu metal.667,669 Formation ofbiaryl by nickel is similar to Ullmann coupling reactions.
3.4.6.1. Ullmann Reaction. Despite some severe drawbacksof the classic Ullmann reaction, such as requirement of highreaction temperature, long reaction times, and high metalloadings (stoichiometric amount or more), the Ullmann
Scheme 213. Structures Synthesized from Persulfuration658−660
reaction has been applied frequently in organic synthesis atboth industrial and laboratory scales.101,670−674 Nevertheless,the actual mechanism of the Ullmann reaction and Ullmanncondensation continues to be debated. Among the mechanismsproposed, there are two pathways generally accepted:667,668 (i)oxidative addition followed by reductive elimination (Scheme215), and (ii) through the formation of an aryl radical by a SET
process (Scheme 216). In the oxidative addition/reductiveelimination mechanism, an ArCuIIX complex is formed in theoxidative addition step, which then disproportionates to formArCuI intermediates. Reductive elimination results in biarylformation. Many of these ArCu complexes are stable at room oreven higher temperature. They have been isolated and furtherreacted with aryl halides to produce biaryl.667,668,675,676 Forinstance, heating solid C6F5Cu under argon afforded thecorresponding biaryl product along with copper metal, whichsupports the oxidative addition/reductive elimination mecha-nism.676
However, studies on Ullmann reaction on surface havedemonstrated that it involves a SET mechanism (Scheme216).208 Evidence of a radical pathway via SET mechanism inthe Ullmann reaction in solution has been reported fromdifferent laboratories. For instance, in the coupling experimentof 2,6-disubstituted aryl halides to form biaryl, the addition ofradical trapping agents decreased the yield.677 Similar resultswere obtained in CuO2-mediated coupling reaction of arylhalides.667,678 More evidence for the involvement of a radicalmechanism was obtained when Rapson’s laboratory679 showedthe formation of biphenyl-2-carboxylic acid and biphenyl-4-carboxylic acid by treatment of iodobenzene vapor with Cu0 inthe presence of ethyl benzoate followed by hydrolysis. Theformation of these products can be explained by theinvolvement of an aryl radical intermediate that undergoeshydrogen atom abstraction from ethyl benzoate. Becausereductive dehalogenation of ArX by SET process in SRN1reactions is a stepwise mechanism and proceeds via formationof ArX−·, it is proposed that the dissociation of ArX is stepwisefor the Ullmann reaction as well.679
3.4.6.2. Ullmann Condensation and Ullmann−GoldbergReaction. The Ullmann condensation and the Ullmann−Goldberg reaction, which were originally reported for thesynthesis of biaryl ethers and biaryl amines, have beendramatically modified (Scheme 217). A breakthrough in this
field came in 2001 when Buchwald laboratory demonstratedthat the use of a diamine as auxiliary ligand improves thesolubility of the copper precursors generated in the course ofthe reaction, and the coupling of aryl halides and amides can beperformed under much milder reaction conditions, such as attemperatures lower than 100 °C, with 5−10% Cu catalysts, andtolerance for many functional groups such as −OH, ester, andketones.670,680
In the modified Ullmann condensation reaction, copper inthree different forms, Cu0, CuI, and CuII, can act ascatalysts.681−684 This finding aroused debate about whichoxidation state of copper is present as the active catalyst.681−684
Various research groups have proposed that soluble cuprousion ((CuI)+) is the true catalytic species. This hypothesis wassupported by the synthesis of stable and soluble CuI complexes,which can serve as efficient precatalysts in copper-catalyzed C−X (X = C, O, N, S) bond formation reactions.685 Regarding thepathway of modified Ullmann reactions, two possibilitiesexist.684 One pathway begins with oxidative addition of arylhalides on CuILX (L = auxiliary ligand), while in the otherpathway oxidative addition happens to CuILNu after thedisplacement of X− by the nucleophile. Most data support thehypothesis that at first the nucleophile coordinates to the CuI
center and subsequently the activation of aryl halide takes place,which is usually the rate-limiting step.683
There are four plausible mechanisms proposed to explain thearyl halide activation step after formation of the ArNu complex:(i) through radical intermediates, which involve a SET processand undergo a CuI/CuII catalytic cycle; (ii) oxidative addition/reductive elimination processes via a CuI/CuIII redox catalyticcycle; (iii) σ-bond metathesis; and (iv) π-complex formation.Among them, the first two pathways are more widely accepted.In the first case, a SET process takes place from aryl halide toCu−-nucleophile complex (LCuINu, Scheme 218),683 yieldingan aryl halide radical anion and CuIIY−R complex. The arylradical then couples with the nucleophile and the CuII gets
Scheme 215. Proposed Mechanism of Ullmann Reaction byOxidative Addition/Reductive Elimination676
Scheme 216. Proposed Mechanism of the Ullmann Reactionby SET Mechanism679
Scheme 217. Modified Ullmann Reaction
Scheme 218. Mechanism of Modified UllmannCondensation via SET683
reduced regenerating the catalyst and releasing the coupledproduct.Recently, evidence for the involvement of a radical
mechanism in Ullmann condensation was also reported byvan Koten and co-workers (Scheme 219).684,686 They prepareda family of aminoarenethiolato−copperI complexes (CuISAr)instead of adding an external ligand as precursor for N-arylationwith aryl halide derivatives.684,686
Surprisingly, in these reactions, aryl bromides were moreactive than iodides, and by using radical traps the reaction canbe slowed or even stopped completely. To explain thisobservation, the authors proposed that the mechanism involvesa SET process from the CuI precursor to the aryl bromide. Thisstep generates an aryl radical and CuII species, and in thesubsequent step, the aryl radical couples with the amine moietywith a second SET process that regenerates the CuI species(Scheme 220).684
In this context, a recent comprehensive study using DFTcalculations by Houk, Buchwald, and co-workers687 is note-worthy. In this study, the authors proposed four possiblemechanisms for activation of aryl halide by LCuINu precursor,where L = ligand (diketone or phenanthroline) and Nu =nucleophile (methanol or methylamine) formed in the initialstep of the coupling reaction between iodobenzene andmethanol or methylamine. They showed that the rate-determining step involves the reaction with the aryl iodide,and this step was calculated for all four mechanisms (Scheme221).687 Their calculation revealed that the mechanism of arylhalide activation step could involve either a SET or an ATmechanism, which is determined by the electron-donatingability of the ligand and the nucleophile. When the electron-rich diketone is used as ligand, the activation step involves aSET mechanism for both methanol and methylaminenucleophiles. However, when phenanthroline is used as aligand, the AT and SET mechanisms have similar barriers, andeither may occur depending on the nucleophile. For instance,using phenanthroline as ligand, the activation of aryl halide withCu I (me thox i d e ) p ro ceed s v i a AT , wh i l e w i t hCuI(methylamido) it proceeds via SET.Another advancement in the field is the photocatalyzed
Ullmann-type reaction, which emerged as an excellent tool forC−C and C−heteroatom bond formation under mild reactionconditions (Scheme 222).688−692 In all of these cases, theinvolvement of a SET process has been proposed. Recently,
Peters, Fu, and co-workers have reported the photoinducedcopper-catalyzed cross-couplings of thiols with aryl halidesunder mild conditions (0 °C).32 The intermediate formed bythe reaction of copper species with the thiol substrate wasidentified by an ESI−MS study, which showed signals for[Cu(SPh)2]
− and [Cu2(SPh)3]−. The authors demonstrated the
involvement of a SET process for the activation of aryl halideby carrying out a radical clock test. A general mechanism for thephotoinduced Ullmann-type cross-coupling reaction proposedby the same group is given in Scheme 222.692,693
The Ullmann-type coupling reactions were reviewedextensively over the years, both concerning reaction method-ologies and mechanism.670,673,674,684,694 The synthetic develop-ment and application of the Ullmann reactions was revieweduntil May 2013.695 Progress after May 2013 includes thesynthesis of chiral amino acid anilides by ligand-free Ullmann−Goldberg reaction (Scheme 223).696
3.4.6.3. The Reaction of Alkyl and Aryl Halides withAtomic Metal Vapors in Solution at Low Temperature. Themajority of organic reactions mediated by metals are eithercarried out heterogeneously on surfaces, or with homogeneousmetal−ligand complexes. The complexity of solid−liquidsurfaces and the presence of ligands complicate the mechanisticstudies. Using atomic metal species in reactions provides aunique way to illustrate the reaction mechanism of metal atomswith alkyl and aryl halides. Atomic metal species can beobtained by evaporating the metal in high vacuum at an
Scheme 219. Coupling Reaction by CuI Complex asPrecursor684,686
Scheme 220. Mechanism of the Coupling Reaction by CuI
Complex as Precursor684,686
Scheme 221. Proposed Mechanisms for Activation of ArylHalide by LCuINu Precursor687
Scheme 222. Photoinduced Ullmann Coupling Reaction ofAryl Halides and the Proposed Mechanism692,693
elevated temperature.697 The metal atoms can either co-condense with the substrate or condense in a degassed solutionof the substrate at a low temperature.697 Low-temperaturestudies ensure the low pressure inside the reaction vessel.Moreover, the reaction is slowed at low temperature, enablingthe observation of a key reaction intermediate by spectroscopicmethods.697
To demonstrate the unusual synthetic application of atomicspecies, one example of synthesis with carbon atom clusters isshown in Scheme 224.698
Timms’ laboratory reported in 1968 the reaction of atomicCu vapors with BCl3 and observed the reductive dehalogena-tion reaction and formation of B2Cl4.
699 Later, Ag, Ni, as well asAu vapors were applied to the reductive dehalogenationreaction of BCl3.
697 Meanwhile, ethyl bromide was dehalo-genated at −196 °C by Cu, Ag, and Au vapors. The couplingproduct butane as well as disproportion product wereobtained.700 The reaction is illustrated as in Scheme 225.
The formation of the coupling product as well as theelimination product support the hypothesis of alkyl radicalintermediates during this reaction.700 The progress of theorganic reaction with metal vapors was reviewed in 1975.697,701
Atomic Cu generated from reduction of CuI·PEt3 with lithiumnaphthalide also reacted with aryl, alkyl, and vinyl halides andproduced organocuprous species. The organocuprous specieswere reported to react with alkyl halides. However, themechanism for the generation of organocuprous species was
not discussed.676 Chanon’s group reported the formation ofbenzene and biphenyl by reacting 3d transition metal vaporswith p-bromotoluene in methylcyclohexane solution.106 Cr wasfound to be most effective in dehalogenation reactions, while Niwas the most reactive for homocoupling reaction. Fivemechanisms were considered. A SET pathway was initiallyruled out because the colors of transition metal vapor/bromotolunene mixture and Na/bromotolunene mixture weredifferent. The authors concluded the process was atomtransfer.106 However, in a later publication from the samegroup, the authors changed their opinion and proposed that theformation of alkyl radicals proceeded by a SET mechanism.The reductive and coupling of monohalobenzenes pathwaysmediated by Cu and Ni vapors was reported. It was found thatCu favors an atom-transfer pathway, while Ni favors anoxidative pathway. Therefore, reactions mediated by Cugenerated benzene as the major product, while biphenyl wasthe major product when Ni vapor was used. The reactionmechanism proposed is depicted in Scheme 226.103
The reaction of substituted bromobenzene with atomic Cuvapors at −108 °C generated products from reactions ofsubstituted phenyl radicals (Scheme 227).702 Cu(PMe3)3Br wasisolated after the addition of PMe3 demonstrated CuIBr is lessreactive than atomic Cu0 in activation of alkyl halides. Thisresult confirms that Cu0 was oxidized to CuI in this reaction, inagreement with studies of benzyl halides with copper powdersin solution.200,703 Moreover, despite the ligand added, the ratioof the products does not change, which indicates that thephenyl radical was the intermediate for the products instead oforganocuprous species.702 The condensation of atomic Cuvapors in anisole resulted in Cu aggregates, indicating Cu wascoordinating with Br instead of π system. It is noteworthy tomention the size-dependent reductive potential of Cu led theauthors to propose that SET generates phenyl radicals inreaction.702 The reductive potential of atomic Cu0 is −2.7 Vversus NHE in H2O as compared to the >0 V reductivepotential versus NHE in H2O of bulk Cu0. The atomic Cuspecies are much better SET donors as compared to bulk Cu.These results demonstrated that the reaction betweenhaloarenes and atomic copper vapor proceeds at −108 °C viareductive dehalogenation of the halogen of haloarenes withformation of CuBr and aryl radicals via a SET mechanism. Thearyl radicals account for the organic products. These results arein agreement with the mechanism proposed for the Ullmannreaction carried out on the Cu(111) surface.208
Egorov’s laboratory studied the mechanism of the reaction ofbenzyl halides with zero-valence metals.703a,704 The study canbe divided into two parts, low-temperature reactions with metalvapors as well as high-temperature reactions with metal surfacein solution. The reaction of metal vapors will be discussed inthis section, while the reactions of metal surface will bediscussed in following sections in more detail.Ti,705 Ni,704b Cu,704c Zn,704a as well as Mn706 were reacted
with benzyl bromides at −123 °C. The reactions of Cu withbenzyl chloride as well as bromides were studied extensively inpolar aprotic solvents.200,703,704c,707 Homocoupling productswere detected after the solution was defrozened. The reactionof Cu vapors with benzyl chloride was provided as an exampleto illustrate the reaction mechanism (Scheme 228).The reaction mechanism as well as product can be applied
for all substrates and metal cases.3.4.6.4. Ullmann Reaction with Alkyl Halides in Solution.
Egorov’s laboratory in Moscow studied the reaction of CCl4
Scheme 223. Copper-Catalyzed C−N Coupling of ArylHalides and L-Phenylalaninamide
Scheme 224. Reaction of Carbon Atomic Clusters withOlefins
Scheme 225. Reaction of Ethyl Bromide with Atomic MetalVapors700
with copper in dimethylacetamide (DMAA).707d The reactionbetween copper and CCl4 was carried out with high-purityreagents. The copper powder was prepared from reduction ofCuSO4 with Mg. By this methodology, C2Cl6 was obtained in95% yield. A white powder was also produced. The whitepowder was recrystallized from 3-MePy and was determined tobe the complex CuCl(3-MePy)3 by elemental analysis and IRspectroscopy. The reaction can be represented as in Scheme229.
The reaction of Cu with CCl4 was proposed to proceed via aSET mechanism. Experimental proof includes (a) disappear-ance of ESR signal of TEMPO species added in reactionmixture; (b) when 6 equiv of DCPH was added, CHCl3 insteadof C2Cl6 was obtained; and (c) formation of CCl3Br whenCuIIBr2 was added in the reaction mixture.The reaction mechanism is shown in Scheme 230. The same
conclusion was reached for the reaction of copper with CCl4 inDMF.200
Reaction between Cu0 powder and benzyl bromide inDMAA was studied both in solution and on Cu0 surface.703a
For the reaction in DMAA solution with >99.99% purity Cu0
powder, the study of the kinetics of the oxidative dissolution ofCu0 by the benzyl bromide was studied using the resistometricmethod. The dependence of the reaction rate on theconcentration of benzyl bromide indicates that the processfollows a Langmuir−Hinshelwood mechanism708 with adsorp-tion of the reagent and solvent at the active centers of the metalsurface (Scheme 231). The Langmuir−Hinshelwood mecha-nism is a surface chemistry phenomenon where a bimolecularreaction occurs via two adsorbed molecules on surface activesites.
The reaction for a surface-mediated reaction is derived as inScheme 232. L is the solvent; K1 and K2 are the equilibrium
constants for the adsorption of benzyl bromide and solvent,respectively; k is the rate constant of the chemical process; S1and S2 are the active sites on Cu0 surface at which theadsorption of benzyl bromide and DMSO, respectively, takesplace; and N1 and N2 are the number of active centers on Cu0
surface.By surface chemistry methods, the benzyl radical was
observed by ESR at −195 °C when benzyl bromide wasadsorbed on Cu0 surface and the signal intensity decreased asthe temperature increased. To confirm the radical formation insolution, TEMPO and DCPD were added to the reactionmixture separately. No ESR signal was observed for TEMPO,and deuterotoluene was detected. This evidence confirmed theSET mechanism.The same process was carried out for substituted benzyl
bromide with copper in DMF,707a HMPA,703b and other
Scheme 226. Reaction Mechanism Proposed for Formation of Benzene and Biphenyl from Monohalobenzene with Metal Vapor
Scheme 227. Reaction of p-Bromoanisole with Cu Vapors
Scheme 228. Reaction of Atomic Cu Vapors with BenzylChloride707b
Scheme 229. Reaction of Cu with CCl4707d
Scheme 230. Mechanism of the Reaction of Cu0 with CCl4200
Scheme 231. Ullman Reaction of Benzyl Bromide withCopper Powder707c
nonpolar dipolar aprotic solvents including hexane, benzene,nitrobenzene, benzonitrile, acetonitrile, 1,4-dioxane, propylenecarbonate, methyl acetate, acetone, ethyl acetate, diethyl ether,tetrahydrofuran, trimethylphosphate, tributylphosphate, di-methyl sulfoxide, triethylamine, and pyridine.707c The SETreaction was found to be the fastest in DMSO. The activity of asolvent is determined by the donor number in the reactionunder consideration. The reaction of copper with benzylbromide takes place in DMSO, DMF, DMAA, and HMPA at80 °C.704c
The reaction of substituted benzyl chloride with copper inDMF was also studied with the same technique. Other than theevidence collected from kinetics, ESR observation, and trappingof radical species by DCPC, the Hammett constants weremeasured. Because benzyl chloride and DMF showed similarionization potentials, the adsorption potentials of bothcompounds are similar. The Hammett constants of ninedifferent aryl chlorides were collected and determined to beconsiderably lower than the values for ionic reactions, but closeto the reaction of tributyltin radical and benzyl chloride inbenzene. Hence, the reaction was proposed to proceed via aradical mechanism. The creation of the radical was furtherconsidered. The formation of isomerized products showed thatthe reaction proceeds according to a radical mechanism insteadof the formation of organocuprate species. Moreover, theabsence of 4-benzyl-1-methyl-benzene in product showed theisomerization of benzyl radical occurs in radical pair only. ESRstudies confirmed the presence of the benzyl radical. Thesurface reaction of benzyl chloride on Cu0 surface when DMFwas coadsorbed was then studied. By the application of a chiralsubstrate, the inversion of chiral center was observed. Thisresult concluded that the SET of Cu0 to benzyl chloride followsa dissociative mechanism (Scheme 233).
Other metals studied by the same author using the sametechnique include Ti, Mn, and Zn.704a,b,705,706
On the Mn706 surface, the reaction follows a radicalmechanism as evidenced by the formation of 1,2-diphenyl-ethane and traces of 4,4′-ditolyl. The benzyl radical wasobserved by ESR. Addition of TEMPO removes the ESR signaland the addition of DCPC produced deuterotoluene. All ofthese data confirmed the SET pathway mechanism. The sameconclusion was obtained for Ti705 and Zn.704a
3.4.6.5. Ullmann Reaction and Polymerization Reactionon the Surface of Cu(111). The importance of the Ullmann
reaction in synthesis triggered a great deal of attention tounderstand its mechanism. Because Cu0 is considered to be theactive catalyst, surface chemistry offers a potential tool to studythe mechanism with spectroscopy tools developed for surfacechemistry. Although reactions taking place on Cu0 surface inthe absence of a ligand are not identical to reactions precedingin solution in the presence of a ligand, additive, and solvent, thestudy on Cu0 surface provides an elegant method to elucidatethe real mechanism.In the 1990s, surface scientists started to study the formation
of biaryls on the Cu0 surface.709 Iodobenzene was adsorbed onCu(111) surface. Two adsorption regions were observed. In thelow coverage region, at −98 °C, iodobenzene dissociates into aphenyl radical or a phenyl copper species. Biphenyl wasdissociated at above 27 °C. In the high coverage region,biphenyl formation was efficient at temperatures as low as −63°C from phenyl radicals and iodobenzene molecule. Theiodobenzene is required to orientate away from the Cu(111)surface so that the phenyl radical will attack iodobenzene andform biphenyl (Scheme 234).710
Following this study, biphenyl group formation on theCu(111) surface was induced by a scanning tunnelingmicroscope tip.711 The process can be described as follows:(a) iodobenzene was first adsorbed on the Cu(111) surface;(b) the STM tip contacts one iodobenzene molecule; (c) uponcontact, the tip of the STM injects one electron (1.5 eV) intoiodobenzene via SET and subsequently the generated radicalanion will facilitate the cleavage of the C−I bond; the process isrepeated again to another iodobenzene molecule; (d) the twophenyl radicals formed in step c are brought close to each otherby the STM tip and an electron-induced bond formationprocess was carried out; and (e) the formation of biphenylmolecule can be demonstrated by dragging one side of themolecule on the Cu(111) surface and observing the movementof the other phenyl ring.711
The Weiss laboratory determined the reactive intermediatesin Ullmann homocoupling of 4-fluorophenyl bromide on the
Scheme 233. Ullmann Reaction of Benzyl Chloride withCopper Powder707b
Scheme 234. Mechanism of Ullmann Reaction on SurfaceProposed Before the Year 2000
Cu(111) surface by STM. Only fluorophenyl radicals andadsorbed bromine atoms (as called adatoms by surfacechemists) were observed on Cu(111) surface when p-FC6H4Br was adsorbed at high coverage.712
Some critical experiments were reported in 2011; theorganometallic intermediate involved in surface Ullmannreaction was imaged at single-molecule resolution. First, arylhalides adsorb on the Cu(111) surface and assemble into anetwork structure. Next, the aryl radicals form a linear structurewith Cu atoms linked between two aryl radicals. At 27 °C, thebiaryl bond will form, and at 127 °C, the CuI dissociates fromthe surface (Scheme 235).208
3.4.6.6. Application of Ullmann Reaction to SurfacePolymerization. The success of biaryl compounds’ formationon the Cu(111) surface led to the development of polymersynthesis on the surface of Cu(111). Because of the surfacetemplate effect, different polymer topologies can be achievedand visualized by STM.In 2004, the Weiss laboratory713 reported the formation and
manipulation of protopolymer chains on the Cu(111) surface.Protopolymer, as defined by the author, are the monomer unitsof a polymer arranged, aligned, but not yet reacted to their finalform. Diiodobenzene adsorbed on surface dissociates tophenylene; phenylene adsorbs on surface defects at lowcoverage. Intermolecular strength is strong enough to holdthe chains together while being moved by the STM tip. Thework showed the potential of polymer synthesis guided byintermolecular strength. In 2009, the formation of linear andzigzag polymers from 1,4-diiodobenze and 1,3-diiodobenzenewas reported. In the case of 1,3-diiodobenzene, macrocycleswere obtained (Scheme 236). CuI formation on surface wasconfirmed by X-ray photoelectron spectroscopy of theiodide.714
A systematic study on the mobility and reactivity ofprecursors on metal surface was published in 2010. Thehexaiodo-substituted macrocycle cyclohexa-m-phenylene wasadsorbed and polymerized on Cu(111), Au(111), and Ag(111)surfaces (Scheme 237). The macrocycles form a linearsupramolecular structure on the Cu(111) surface, 2D domainson Au(111), and well-ordered 2D domains on the Ag(111)surface. The source of the differences between different
domains structure was studied by DFT, and it was concludedto be the energy of the mobility of radicals on differencesurfaces. On the Cu(111) surface, the energy for the radical tomove is the largest; hence a more linear structure wasformed.715
Another very important development of these experiments isthe synthesis of graphenes with diameter of less than 10 nm onthe surface of Cu(111) with precise control. The synthesis wascarried out on the surface of Cu(111) by surface-mediatedUllmann coupling followed by dehydrogenation (Scheme 238).The bottom-up strategy gives atomic control of the graphenenanoribbons.716
Although surface polymerization is a relatively young field,the work has been reviewed until October 2011.717 Linlaboratory observed the supramolecular assembly of bis-terpyridine tetraphenyl ethylene on Cu(111) surface. Themolecules self-assemble to triangular metallacycles, propellertrimeric clusters, and extended linear chains by metal−ligandcoordination, van der Waals interactions, and hydrogenbonding.718
The synthesis of graphene on Cu(111) surface was alsocarried out with hexabromobenzene at 220−250 °C. Thecoupling was described as a radical process following Ullmancoupling mechanism. In recent work, the surface-assistedorganic synthesis of hyperbenzene nanotroughs was reportedby Gottfried laboratory (Scheme 239).719 4,4″-Dibromo-1,1′:3′,1″-terphenyl was used as the precursor monomer, andits polymerization provides zigzag polymers with a unifiedtexture.719
Scheme 235. Mechanism of Ullmann Reaction on Surface208
Scheme 236. Formation of Linear, Zigzag MacrocyclicPolymers and Oligomers on Cu(111) Surface714
Scheme 237. Formation of Macrocycles on Cu(111)Surface715
3.4.6.7. Nickel-Catalyzed Ullmann-like Coupling andPolymerization. Nickel catalysts were used in Ullmann-likereaction since 1966, when Saito and Yamamoto reported the
formation of butane during the decomposition ofEt2Ni
II(bpy).720 In 1971, Semmelhack reported the firsthomocoupling reaction of aryl halides by stoichiometricNi(COD)2 in DMF at 25−45 °C.721 Kumada and co-workersachieved the first case of homocoupling of aryl halides mediatedby a catalytic amount of nickel in the presence of Zn in 1977.722
Aryl sulfonates are also applied in homocoupling.723 Althoughquite a number of studies were carried out on nickel-catalyzedUllmann-like reactions, the mechanism for homocoupling isunder debate. Initially, Semmelhack proposed the 2 ArX + Ni0
→ ArX + ArNiIIX → Ar2NiIVX2 mechanism to account for the
generation of biaryl.721 However, Kochi proposed a differentmechanism involving NiI and NiIII radical chain mechanism(Scheme 240).212 In this mechanism, one ArX reacts with Ni0
to form NiII, while another ArX molecule reacts with NiI togenerate NiIII. Aryl−halide exchange followed by reductiveelimination generates the biaryl products. However, the originof the NiI species was not understood. One possibility proposedby Kochi involves an SET process (Scheme 241).
Rieke proposed a different mechanism involving a NiII
complex metathesis as the key step (Scheme 242).724 Themetathesis or disproportion step is supported by the generationof biaryl in the thermal decomposition of ArNiIIXL.
Colon proposed the generation of NiI via SET from Zn toNiII (Scheme 243).It is possible that both Kochi and Colon mechanisms are
operating. With excess Zn, the Colon mechanism is more likelyto occur. However, with limited Zn, the Kochi mechanism ismore plausible.726 For a more detailed discussion onmechanism and structures synthesized from the Ni-mediatedUllmann-like reaction, the readers are referred to a recent
Scheme 238. Formation of Graphene Nanoribbons onCu(111) Surface716
Scheme 239. Synthesis of Hyperbenzene Nanotrough viaUllmann Reaction on Cu(111) Surface719
Scheme 240. Mechanism of Nickel-Catalyzed Homocoupling
Scheme 241. Generation of NiI
Scheme 242. Mechanism of Nickel-Catalyzed Homocoupling
review.725 Although no unified mechanism was proposed forNi-mediated Ullmann-like reaction, great progress has beenmade over the years such as development in C−O substratesand the application of this reaction in PPP synthesis.725 Inattempts to synthesize oligomers and polymers from Ni-catalyzed Ullmann-like reactions,726 aryl sulfonates instead ofaryl halides were used. Further study showed a wide range ofsulfonate leaving groups are active in Ni-catalyzed homocou-pling reaction (Table 6).723 In the case of 4-chlorophenylsul-fonyl leaving group, the low yield was obtained due to theparticipation of Cl in the leaving group (Table 6, entry 3).
Biaryl monomers were synthesized from Ni-catalyzedhomocoupling reactions (Scheme 244)727 and applied in thesynthesis of HH-TT regioregular polymers (Table 7).728
The presence of alkyl-side chain increases the solubility ofthe polymer, and hence increases the yield of the polymer-ization. The copolymerization of substituted MsOArArOMswas also studied in detail (Table 8).3.4.7. Gomberg−Bachmann−Hey Reaction. In 1924, in
an attempt to prepare 4-bromobiphenyl, Gomberg andBachmann, inspired by results previously published byBamberger, developed a new method for the synthesis ofasymmetric biaryls.730 The reaction is called the Gomberg−Bachmann reaction. This reaction refers to coupling of aryldiazonium salts with arenes under basic conditions (Scheme245).
Without the isolation of explosive dry diazo oxides, the insitu reaction is nonexplosive and scalable up to 100 g. Theweakness of this reaction is the low yield. Only 12−40% yieldwas isolated for biaryl complexes. Hence, after the developmentof transition metal-catalyzed cross-coupling reactions, theGomberg−Bachmann reaction became less frequently used inorganic synthesis.The intramolecular version of this reaction was discovered in
1896 by Pschorr and was named the Pschorr reaction. After 10years of Gomberg and Bachmann’s first publication,730 Grieveand Hey modified the original reaction conditions by usingsodium acetate instead of sodium hydroxide.731 The yield withnitroanilines, o-chloroaniline, and ß-naphthylamine increasedsignificantly, while for other substrates, inferior yields wereobtained. The progress of arenediazonium salts chemistry hasbeen reviewed last in 1973.732
A significant piece of progress in the last decades is thedevelopment of the PTC Gomberg−Bachmann−Hey reaction.The original Gomberg−Bachmann−Hey reaction uses aryldiazonium salts in aqueous phase as obtained to avoidexplosions. In 1984, it was proposed that the low stabilityand low solubility of the diazonium salts lead to the low yield ofthe reaction. Arenediazonium tetrafluoroborate and hexafluor-ophosphate salts were proved to be isolated in high yields andwere shown to be safe for storage. However, their low solubilityin nonpolar organic solvents inhibits their utility. Crown-ethers,quaternary onium salts, and lipophilic carboxylic acid salts usedas phase-transfer catalyst were reported to increase the yield ofthe Gomberg−Bachmann−Hey reaction.733 The mechanism ofthe Gomberg−Bachmann reaction was elucidated before the1960s. The commonly accepted pathway is a series of radicalfragmentations and addition reactions (Scheme 246).734
However, in 1997, Kochi described the iodine-catalyzedmodified Gomberg−Bachmann reaction of pentafluorobenze-nediazonium cation as a SET-mediated chain reaction.735 Themodified reaction mechanism involves a chain initiation by SETfrom iodide to aryl diazonium cation and a series of radicalchain reactions. Other initiators described include the Cp2Fecomplex, Zn granules, and the aromatic donor, p-dimethox-ybenzene. It was observed that the addition of a small amountof iodide promotes the complete and efficient biaryl coupling ofbenzene and pentafluorobenzenediazonium cation. However,the presence of O2 retards the reaction. Electron-rich substrateswere found to be more reactive than electron-deficientsubstrates. The reason for the aromatic donor being capableof catalyzing this reaction was traced down to the SET from theelectron-deficient pentafluorobenzenediazonium cation to theelectron-rich aromatic donor as observed by UV−vis. Thereaction can also be induced by photons. Upon irritation withvisible light, the SET between arene and pentafluorobenzene-diazonium cation happens, followed by a series of radical chainreactions (Scheme 247).735
The modern Gomberg−Bachmann reaction still has the limitof low regioselectivity. However, other radical sources haveappeared including aryl boronic acids and hydrazines.Heteroarenes are also used as substrates. Also, other radicalinitiators including Bu3SnH and (TMS)3SiH were used in thisreaction.736
In 2008, Heinrich’s laboratory demonstrated the TiCl3-initiated Gomberg−Bachmann radical chain reaction for thesynthesis of amino and hydroxybiphenyls from arenediazoniumsalts.737 Reaction was carried out with 0.5 equiv of radicalinitiator. As was observed by Kochi laboratory, electron-rich
Scheme 243. Mechanism of Homocoupling Catalyzed by Niin the Presence of Zn725
Table 6. Ni(0)-Catalyzed Homocoupling of Various p-Carbomethoxyphenyl Sulfonatesa723
entry leaving group X reaction time (h) GC yieldb (%)
substrates produced higher yields. High ortho/para selectivitywas observed in selected cases. The method was used for thesynthesis of fungzide Boscalid (Scheme 248).Copper-catalyzed coupling of aryldiazonium tosylate was also
reported.738 The salt was prepared from aniline and a p-tosylsulfonyl acid. The reaction was carried out at 50 °C.Moderate yields were obtained for 15 anilines with bothelectron-withdrawing and electron-donating groups.738 Thedevelopment of the radical Gomberg−Bachmann reaction also
enabled the arylation of anilines with aryl diazotates. Freeanilines were used without protection, and the yields were 34−68%. The regioselectivity issue of the Gomberg−Bachmann−Hey reaction was not resolved yet.739
3.4.8. Pschorr Cyclization. The intramolecular coupling ofaryldiazonium salts with arenes under strongly acidic conditionsor in the presence of copper is called the Pschorr reaction(Scheme 249).740
In the early 1970s, there were still some arguments on themechanism of the Pschorr reaction. Two different reactionmechanisms were reported for the Pschorr reaction underdifferent reaction conditions.736 In acidic or neutral conditions,the abstraction of proton from solvent was observed. Thereaction of benzene diazonium salts with methanol generatesanisole and supports a cationic mechanism (Scheme 250).However, in the presence of copper or under electro-
chemistry conditions, the Pschorr reaction proceeds via a SETmechanism (Scheme 251). In 1971, Elofson and co-workersapplied electrochemical methods in the reduction of diazoniumsalts of 2-amino-α-arylcinnamic acids. Higher than 90% yieldwas obtained regardless of the property of the substituent.Iodide, bromide, and copper powder were all found to increasethe yields of the Pschorr reaction as compared to the thermalinduced reaction. The redox potential of aryl diazonium saltswas compared to a series of single electron donors. The redoxpotential of diazonium salts is lower than I−/I2, Cu
0/CuI, andCuICl/CuIICl2, but higher than CuIBr/CuIIBr2. This explainedthe reaction that Cu powder and iodide facilitated theGomberg−Bachmann reaction by the SET mechanism. More-over, it was also proposed that Pschorr reactions performed inthe presence of bromide proceed by a SET mechanism. Furtherstudies in the Elofson laboratory showed that the previousheterolytic mechanism is actually an intermolecular SETprocess induced by homolytic cleavage.741
More than one century after its discovery, the Pschorrreaction became one of the most important and reliablemethods to prepare polycyclic aromatic hydrocarbons.102 Themost important recent progress will be highlighted here.Soluble catalysts instead of copper powder were developed to
increase the yield of the Pschorr reaction. As described in theGomberg−Bachmann reaction, the low solubility of aryldiazonium salts in aqueous reaction mixture as well as theheterogeneous catalysis of copper both lead to diminished yield
Scheme 244. Synthesis of Bismesylates of 2,2′-Diaroyl-4,4′-dihydroxybiphenyls (7a−c)727
of the Pschorr reaction. Surveys of soluble catalysts includedFeSO4, FeSO4/H3PO4, K4Fe(CN)6, hydroquinone, andferrocene. Ferrocene was found to be a very effective catalyst,achieving 91% yield in 5 min at 10% loading as compared to27% yield after over 80 h in the absence of catalyst.742 Also, aphotocatalyst was developed for the synthesis of phenanthreneseries.589 A yield of 100% as determined by HPLC wasobtained when Ru(bpy)3
2+ was applied as photocatalyst.Spectroscopic data indicate that Ru(bpy)3
2+ does not degradeafter the reaction is over. The mechanism can be illustrated asshown in Scheme 252.
A very important proof for the radical mechanism is theobservation of intramolecular aromatic 1,5-hydrogen trans-fer.743 The reaction is shown in Scheme 253.This rearrangement was also observed in the Sandmeyer
reaction.743 The problems associated with this rearrangementand regioselectivity are one of the current synthetic limitationsof this aromatic radical chemistry.3.4.9. Base-Promoted Homolytic Aromatic Substitu-
tion. C−H activation is the most atom-economic C−Ccoupling formation reactions. Great progress in C−H bondfunctionalization has been achieved recently and applied in thesyntheses of natural products and pharmaceuticals.744 However,a simple comparison of bond dissociation energies of Ph−Hbond (110 kcal/mol) with Ph−Cl bond (95 kcal/mol), Ph−Brbond (79 kcal/mol), and Ph−I (64 kcal/mol) bonddemonstrates the difficulty in activation of C−H bonds inarenes. As discussed in the Introduction, the bond dissociationenergy of a radical anion or radical-cation is much lower thanthat of the neutral species. Hence, C−H activation via SETmechanism is energetically favored.Homolytic aromatic substitution was first recognized by Hey
in 1934.745 The substitution is a radical substitution of aromaticcompounds and was reviewed by Bolton and Williams in1986.746 Lately, Bu3SnH, AIBN, and silanes were used toinduce homolytic aromatic substitution. This work was
reviewed by Bowman and Storey until the year 2007.747
Recent interest in transition metal-catalyzed coupling reactionsled to the discovery of transition metal-catalyzed C−Hactivation and coupling reactions.744a,748 Meanwhile, the base-promoted homolytic aromatic substitution via SET mechanismwas also reported.749 Because of the different chemicalproperties of transition metals and bases, these two types ofC−H arylation will be discussed separately.Numerous transition metals have been applied in C−H
arylation reactions, such as Pd,750 Rh,748a Ru,748c Ni,748b Cu,751
Ir,751 Co,752 Fe,753 and Nb.752 Of these metal-mediated C−Harylation reactions, the mechanism for activation of C−H bondby Pd, Ru, Ni, and Cu catalysts, is believed to be C−Hmetalation.748a,b,750,751 The mechanism for activation of C−Hbond by Rh catalyst is believed to follow a Friedel−Craftsmechanism.748c Hence, they will not be discussed in thisReview.In 2010, Charette and Lei laboratories reported the direct
arylation of aryl iodides and bromides catalyzed by ironindependently.753,754 While the Lei laboratory did not provide adetailed mechanism for their study, the Charette laboratoryproposed that the reaction proceeded via a radical pathway.Yields were moderate to good for electron-rich and -deficientaryl iodides. Diminished yields were obtained for aryl bromides.The C−H activation of arenes is not stereoselective. Stericallyhindered arenes were coupled in moderate yields (Scheme254).753 Galvinoxyl and TEMPO inhibited the reaction, andAIBN was found to promote the reaction. These results led theauthors to conclude that iron-catalyzed direct arylation reactionproceeds via a radical mechanism (Scheme 255).753
Shi’s laboratory studied the catalytic activity of varioustransition metals in the direct arylation reaction.752 Out of 22metal catalysts studied, Co, Nb, and Mo were found to beactive in promoting direct arylation of 4-methoxy phenylbromide. TEMPO as well as SmI2 terminated these reactions.The addition product was observed when 1,1-diphenylethylenewas used as the indicator of radical intermediates. Kineticisotope effect experiments indicated the formation of a radicalintermediate instead of C−H bond cleavage. The mechanismproposed is shown in Scheme 256. Further studies involved thecobalt-catalyzed C−H arylation with aryl iodides and chloridesas well as heteroarenes.755
Iridium was also applied in homolytic aromatic substitutionas a photocatalyst.756 The mechanism follows the pathwayshown in Scheme 256.
Scheme 250. Ionic Mechanism of the Pschorr Reaction736
Important progress of homolytic aromatic substitution wasprovided by the use of organocatalysts.749,757 In 2008, Itami’slaboratory published the C−H activation of electron-deficientnitrogen heterocycles and the coupling reaction with haloarenespromoted by K−OtBu (Scheme 257). A radical mechanism was
observed for this reaction. Addition of TEMPO inhibited thereaction. The mechanism was proposed as homolytic aromaticsubstitution or SRN1 reaction. Later, this methodology wasapplied for the coupling of nitrogen-containing heteroaromaticswith alkanes.758
Three laboratories reported the transition-metal free C−Harylation for unactivated arenes independently.759 N,N-Dimethylethylenediamine (DMEDA)759a (Scheme 258) aswell as 1,10-phenanthroline759b (Scheme 259) were found to
Scheme 253. Intramolecular Aromatic 1,5-Hydrogen Transfer in Pschorr Reaction743
Scheme 254. Iron-Catalyzed Direct Arylation of Arenes753
Scheme 255. Mechanism for Iron-Catalyzed DirectArylation753
Scheme 256. Mechanism of Transition Metal-CatalyzedDirect Arylation756
Scheme 257. C−H Arylation of Electron-Deficient Arenes758
be efficient catalyst for coupling of aryl iodides with benzene inthe presence of KOtBu. Radical scavengers stopped thereaction. While DMEDA was found to be an efficient catalystfor direct arylation of aryl iodides, it was found to be inefficientfor coupling of aryl bromides. 1,10-Phenanthroline wasdiscovered to be the most efficient in the coupling of arylbromides.While Kwong, Lei, and Shi detected the radical character of
the C−H activation, no detailed mechanism was provided intheir original publications.759a,b Hayashi’s laboratory studied themechanism of this base-promoted C−H activation andobserved the radical character for this reaction.759c Consideringthat aryl halides are known electron acceptors and t-BuO− is aknown SET donor, they suggested a homolytic mechanism ofaromatic substitution. Both NaOtBu and KOtBu were effectivein promoting the reaction, but not LiOtBu. The mechanism wasfurther discussed by Studer and Curran.749 With a moredetailed examination, the mechanism was proposed to follow abase-promoted homolytic aromatic substitution induced bySET (Scheme 260). However, the initiation step was not clearaccording to Studer and Curran. KOtBu was proposed to be the
potential SET donor. The role of the organocatalyst wasproposed to be either SET catalyst or redox catalyst.749
Albeit its short history, the base-mediated C−H bondarylation of aromatic compounds was reviewed in 2011, 2012,and 2013.757,760 Therefore, only progress reported afterFebruary 2013 will be discussed in this section. Thetransition-metal free mono-α-arylation of ketones was mediatedby NaOtBu (Scheme 261).761
3.5. Thermal- and Photoinduced SET Mediated by AmineDonors
The first stable amine radical cations were isolated much earlierthan the analogous stable free radical, trityl radical in 1900 byGomberg150 and trityl carbocation salt in 1902 by vonBaeyer,762 respectively.142 These amine radical cation saltswere isolated in 1879 by Casimir Wurster.763,764 These amineradical cation salts are now known as Wurster’s Red and Bluesalts (Scheme 262). In 1926, Weitz isolated another aromatic
aminium radical cation, the triarylaminium perchlorate(Scheme 262).138 Wurtz also coined the terms “radical cation”and “aminium” ion to describe the nature of these species.138
Nonaromatic aminium radicals were first reported in theearly 1880s by A. W. Wawzonek during the Hofmann−Lofflerpreparation of N-methylgranatanine.143,765 In this seminalpublication, he reported that the treatment of 1-bromo-2-propylpiperidine with hot sulfuric acid, followed by basic work-up, resulted in the formation of a cyclized tertiary amine, whichwas later identified as octahydroindolizine (Scheme 263).766
This reaction was extensively studied by K. Loffler and C.Freytag767 who expanded the scope of this reaction to simplesecondary amines. The reaction is now called the Hofmann−Loffler reaction (Scheme 264) and is commonly considered to
proceed by a radical chain process.768 The Hofmann−Lofflerreaction was reviewed most recently in 2013 by R. Sarpong.768
Because of their low oxidative potential, amines are some ofthe most easily oxidized organic substrates. Aminium radicalsgenerated by oxidation of amines by a SET process are highlyreactive intermediates that can react via different pathways: (a)deprotonation at the nitrogen; (b) deprotonation at an α-carbon; (c) intra- or intermolecular hydrogen abstraction; and(d) coupling reactions.144 They can be employed in thesynthesis of various biologically and pharmaceutically importantcompounds, such as amino acids, alkaloids, and various othernitrogen-containing compounds.145 The SET from amine canbe obtained by various methods including chemical methods,photochemical methods, electrochemical oxidation, and radio-lytic oxidation.145 In the chemical methods, a reagent havingsuitable oxidation potential to match the potential of the aminein an inert solvent (e.g., CH2Cl2, MeCN) can result in SETfrom amine. Metal salts such as ceric ammonium nitrate(CAN), manganese oxalate, alkaline ferricyanide, phenanthro-line complexes of iron, and octacyanomalybdate are commonlyused to generate iminium radical cations by thermal oxidation.In addition, the oxidation of amines by chlorine dioxide, N-bromosuccinimide, and N-chlorobenzotriazole has been dem-onstrated to proceed by SET.145 Photoinduced SET is anothercommonly used pathway to generate an aminium radicalcation.144,769,770 The photoredox chemistry of amine radicalcations was reviewed until October 2013.771 Electronicallyexcited states of many molecules are rapidly quenched byamines generating aminium radicals as intermediates andundergo various types of reaction such as N−H or α-CHdeprotonation, halo- and cyano-arene photosubstitutionreactions, photoadditions of amines to CC, COderivatives, etc.143 Moreover, SET of amine in biologicalsystem is also very common.145 This review section will onlyfocus on the SET of amines in organic synthesis. Some of themost common SET reactions of amines involve reductivedehalogenation and subsequent cyclization reactions mediatedby amine donors.3.5.1. Reductive Dehalogenation Reactions Mediated
by Amine Donors. The reductive dehalogenation mediatedby amine donors includes two types, thermal and photoactivated, respectively.
3.5.1.1. Photoinduced Reductive Dehalogenation Medi-ated by Amine Donors. To our knowledge, the firstobservation of reductive dehalogenation reaction mediated byamine was reported in 1961.772 It was demonstrated thatbromotrichloromethane is converted to chloroform in thepresence of amines either in the dark or under light (Scheme265). The light-induced reactions were more reproducible as
compared to those conducted in the dark. The reactionmechanism was proposed to be a free-radical chain reactioninitiated either by heat or by light.772 The initiation process waselucidated.The reductive dehalogenation process was subsequently
studied by spectroscopic methods.773,774An EDA complex wasdetected. The reductive dehalogenation reaction was explainedby SET from amine to halomethanes and sequential cleavage ofthe C−X bond (Scheme 266).774 The bond-breaking ratefollows: C−Br > C−Cl > C−F.773
3.5.1.2. Thermal-Induced Reductive DehalogenationMediated by Amine Donors. Besides Pr3N, 1,3-dimethyl-2-phenylbenzimidazoline (DMBI) was reported to be an efficientreagent for reductive dehalogenation of α-halo carbonylcompounds.775 The reaction proceeded in refluxing THF andreaches complete conversion in as short as 30 min for somecases (Scheme 267).
Scheme 263. Hofmann’s Synthesis of Octahydroindolizine
Scheme 264. Proposed Mechanism for Hofmann−LofflerReaction768
Scheme 265. Reductive Dehalogenation in the Presence ofAmines772
Scheme 266. Reaction Mechanism of ReductiveDehalogenation of Halomethanes by Amines
Scheme 267. Reductive Dehalogenation of α-Halo CarbonylCompounds by DMBI775
The mechanism of this reduction was studied. The radicalinhibitor dinitrobenzene stopped the reaction. Radical inter-mediates were also characterized by ESR spectroscopy tosupport a radical chain reaction initiated by SET from theDMBI to α-haloketones. The cyclization by reductivedehalogenation will be discussed in the cyclization mediatedby amine section.3.5.2. Cyclization Reactions Mediated by Amine
Donors. Besides the cyclization reactions discussed in sections3.1.12 and 3.2.3, cyclization mediated by amine donors viareductive dehalogenation pathway can be activated thermallyand by light.3.5.2.1. Photoinduced Cyclization Reactions Mediated by
Amine Donors. Photoinduced SET from amine gives rise tocyclization reaction under mild conditions.144,769,770 Thiscomprises two types of reactions. One includes the reactionof the amine does not generate a radical cation via thephotoinduced SET process in the presence of a sensitizer, suchas anthraquinone. Subsequently, this reaction results in anamine-containing adduct. For instance, primary, secondary, ortertiary amines upon photo excitation result in C−C bondformation via addition reaction with olefin, α,β-unsaturatedesters, and nitriles producing cyclized products (Scheme268).144,776,777 In addition, direct photo irradiation can also
lead to a SET from amine in the presence of a suitable acceptor.This type of reaction has been reviewed by J. S. D. Kumar andS. Das in 1997.144
On the other hand, amines can also be used as photo-chemical SET donors in various types of photoinduced SETreactions for the generation of reactive radical anions, whichsubsequently undergo synthetically important reactions. Inthese reactions, electronically excited states of many moleculesare rapidly quenched by a SET from amine generating aminiumradicals as an intermediate and undergo various types ofreaction, such as halo- and cyanoarene photosubstitutionreactions, photoadditions of amines to CC, COderivatives, etc.143 In this context, the contribution by Cossyand co-workers, and Mattay and co-workers, is noteworthy.778
For instance, Cossy’s laboratory has reported the stereo-selective synthesis of several bicyclic pentanols by theintramolecular addition of the ketyl radicals of σ,β-unsaturatedketones. In this reaction, the ketyl radical is generated via aphotoinduced SET process from tertiary amines donors(HMPA or TEA) in acetonitrile (Scheme 269).776
Similarly, photoinduced SET has been utilized for thereductive ring-opening of strained ring systems such as incyclopropyl and cyclobutyl ketones. This reaction involvesgeneration of a radical adjacent to the strained ring by SETfrom amine. Cossy reported reductive dehalogenation reactionof alkyl bromides and iodides by photoinduced SET inexcellent yields affording cyclized products (Scheme270).776,779
Stereoselective synthesis of various types of heterocycliccompounds and ring expansion by reactions promoted throughphotoinduced SET by amines were also reported by the J.Cossy laboratory, E. Hasegawa laboratory, and Mattaylaboratory. These reactions have been reviewed by J.Cossy.776,780,781
3.5.2.2. Thermal-Induced Cyclization Reactions Mediatedby Amine Donors. Under thermal reaction conditions, not onlywas the C−Br bond activated by amines, the C−Cl bond alsounderwent reductive dehalogenation and cyclization mediatedby amines.782 Ishibashi’s laboratory reported the radicalcyclization of trichloroacetamides mediated by 1,4-dimethylpi-perazine upon heating in refluxing amines (Scheme 271).783
The cyclization did not occur in amine at room temperature.However, when DMSO was used, the cyclization product was
Scheme 268. Cyclization Reaction by Photosensitized SETof Amine Donors
Scheme 269. Cyclization Reaction by SET upon DirectPhotolysis of Amines
Scheme 270. Reductive Dehalogenation by PhotoinducedSET
Scheme 271. Reductive Cyclization Mediated by Amines783
isolated in 50% yield in contrast to 0% yield when benzene orDCM was used. This can be explained by the known efficiencyof DMSO as an excellent solvent for SET reactions.783
The cyclization mediated by amines was compared toBu3SnH-mediated reactions. It was found the cyclizationintermediate formed by 1,4-dimethylpiperazine attacked ahydrogen atom more rapidly as compared to that generatedby Bu3SnH.
784 Moreover, water was found to promote thereaction.785 The mechanism of the cyclization mediated byamines is concluded to be a classic example of outer-sphereSET-initiated radical cyclization reaction (Scheme 272).784
The cyclization was further used for the synthesis of(−)trachelanthamidine (Scheme 273).786
In addition to amines, dihydroquinone (DBU) is also a goodSET donor that mediates the cyclization reaction in a mannersimilar to that of amine donors (Scheme 274).782
Amines can also act as SET donors to mediate the reductiveaddition of benzenethiyl radicals to alkynes (Scheme 275).787
3.5.3. Recent Progress on SET of Amines. Aminiumradical cations can also act as excellent SET donors in manyradical chain reactions, such as Diels−Alder cycloaddition,radical cation polymerization,788 photosensitized cyclobutana-tion, etc.142 Because these reactions in the presence of aminiumradical cations involve a radical chain reaction, only a catalyticamount (e.g., 5−10%) of oxidant is needed. For instance, atypical Diels−Alder reaction is not efficient unless thedienophile is substantially electron deficient. However, therate of the reaction can be enhanced by the efficient chemical
initiation with the aid of shelf-stable triarylaminium salts underextraordinarily mild conditions (Scheme 276).142
Two recent publications from Ishibashi’s laboratory used thereductive properties of hydrazides for addition reactions(Scheme 277).789 The reaction was carried out in air and
used O2 as oxidant. The yields obtained were moderate to goodfor terminal alkenes. Functional groups tolerated include nitro,aryl, pyridyl, and esters.789 The proposed mechanism isdepicted in Scheme 278.
Scheme 272. Mechanism of 1,4-Dimethylpiperazine-Mediated Cyclization Reactions via SET784
Scheme 273. Synthesis of (−)Trachelanthamidine UsingAmines-Mediated Radical Cyclization786
Scheme 274. DBU-Mediated Cyclization and Aziridine Formation782
Scheme 275. Reductive Addition of the Benzenethiyl Radicalto Alkynes by Amine-Mediated SET787
Scheme 276. Diels−Alder Reaction Induced by SET fromAminium Radical Cations
Scheme 277. Radical Oxidative Addition of Sulfonyl Radicalto Alkenes789
The radical addition to alkenes was also generated from theoxidation of arylhydrazines by FeIII.790 The reaction was carriedout in water at room temperature. The yields were moderate togood. When trisubstituted alkenes were used, mixtures of E/Zproducts were obtained (Scheme 279). The mechanism issimilar to that depicted in Scheme 278. A SET followed by lossof N2 generated the aryl radical.
3.5.4. Organic Super Electron Donors. In 1970, Wudl’slaboratory139 reported the synthesis of tetrathiofulvalene (TTF,Scheme 280). This reagent was followed by the synthesis ofmany other analogous compounds. These compounds havebeen used as neutral organic electron donors producing radicalcations and dications via one and two SET processes,respectively, at rather low redox potentials.140,141,791 The
good electron donor property of TTF is partially attributedto the aromatization energy gain due to oxidation (Scheme 280,a).791 The reaction of TTF and its derivatives with diazoniumcompounds through the SET process is well-established(Scheme 280, b).140,141
On the other hand, tetrakisdimethylaminoethene (TDAE,Figure 11), discovered in 1950 at DuPont,792,793 is another
organic electron donor that has had widespread use since itsdiscovery. In this period, it was also discovered that replacingsome of the sulfur atoms in TTF, such as dithiadiazafulvalenes(DADTF, Figure 11), can provide even stronger electrondonors.794 Based upon this strategy, in 1971 Bourson reportedthe synthesis of tetraazaalkene 4 (Figure 11).795,796 Thereducing property of 4 over TTF and TDAE was due to twofactors: the gain in aromatic stabilization energy upon SET andthe presence of the nitrogen atom that stabilizes the radicalcation. This was followed by several reports on the synthesisand study of the tetraazafulvalene family. For instance, Tatonand Chen reported a stable tetraazafulvalene derivative 5(Figure 11), which is a stronger reducing agent than 4.797,798 In2005, Murphy’s laboratory demonstrated that the donor 6(Figure 11) can reduce aryl iodides as well as alkyliodides.140,141,799,800 This was the first report on the reductionof an alkyl or aryl iodides by a neutral organic donor in theabsence of light and at low temperatures.Another strong reducing agent 7 was reported by Murphy’s
laboratory in 2008.140,141,800,801 It is noteworthy that whiledonor 6 reduces iodoarenes to an aryl radical by a SET process(Scheme 281), donors 5 and 7 result in aryl anions throughtransfer of two SET steps.802
In subsequent reports, it was showed that organic donorswith analogous structures can reduce sulfonamides, gem-disulfones, acyloin derivatives, and Weinreb amide derivativespresumably via sequential SET steps.140 In addition to thestrong reducing properties of these organic electron donors inthe ground state, they can act as even stronger reducing agentsupon photo excitation (Scheme 282). For instance, chlor-
Scheme 278. Proposed Mechanism of Radical Addition of Sulfonyl Radicals Generated by Oxidation of Hydrazides789
Scheme 279. Oxidative Radical Addition of Aryl Hydrazinesby SET Oxidation of Hydrazines790
obenzene can also be reduced by 5 and 7 upon photolysis,which shows no reactivity in the ground state.802,803 Underphotolytic conditions, they also show selectivity in reducing thearene groups. Hence, these amine-based reagents were called“organic super donors”. For example, arenes are known torequire Birch reduction or other metal-derived SET reactions toundergo reduction via formation of radical anions. However, inthe presence of aliphatic ester groups, arenes remain unaffected.Recently, Murphy’s laboratory showed that selective reductionof arenes over malonate and cyanate is possible with photoactivated organic electron donors 4 and 5, which undergo SETto result in selective benzyl-C cleavage.802,803
3.5.5. LRP Mediated by Amines. The history of amine-mediated radical polymerization can be dated back to the early1950s. Horner and co-workers observed that the polymer-ization of some monomers by benzoyl peroxide was accelerated
by amines.804 A SET process was proposed to account for thenitrogen content in the final polymer product (Scheme 283).Later, the same effect was also observed by Kimura’s
laboratory.805 The polymerization of vinyl chloride initiatedby benzoyl peroxide was carried out in THF, ethylenedichloride, dioxane, cyclohexanone, and methyl ethyl ketonein the presence or absence of dimethylaniline (Scheme 284).
The polymerization in the presence of dimethylanilineshowed a higher initial polymerization rate; however, theconversion reached a plateau at lower than 20%. Iodometrictitration carried out to determine the amount of benzoylperoxide in reaction indicated that benzoyl peroxide decom-poses as the reaction proceeds. When the reaction conversionreached a plateau, no more benzoyl peroxide was left in thereaction mixture. Addition of extra benzoyl peroxide resumedthe reaction.805 Kinetics study of polymerization of Stycatalyzed by benzoyl peroxide and dimethylaniline led theauthors to conclude that this reaction was initiated by a SETprocess between aniline and peroxides.806 However, becausethere was ambiguity as to whether nitrogen was found in thefinal polymers, the radical anion of the amine was notconsidered to initiate the reaction. It contributed to theacceleration of polymerization by assisting the generation ofbenzoyl peroxide radical (Scheme 285).806
In 2007, the Tsujii and Fukuda laboratory reported thereversible chain-transfer-catalyzed polymerizations (RTCPs).807
Later, it was discovered that Ge, Tin, and P compounds arereactive for this process. Amines are also reactive for RTCP.808
Common amines such as triethylamine and tetramethylethyle-nediamine (TMEDA) were capable of catalyzing the LRP ofmethyl methacrylate (MMA), Sty, acrylonitrile, and otherfunctionalized methyl acrylates (MA). The polymerization ofacrylonitrile reached 100% conversion in 4 h with PDI = 1.49for DP = 200.808 The mechanism proposed by the authorsincludes the abstraction of iodine atom with amine anddimerization of iodine atoms to form an iodine amine complex(Scheme 286).
Scheme 281. SET by Amines to Aryl Halides
Scheme 282. Photoinduced SET by Organic Super Donors
Scheme 283. SET of Amine-Initiated Radical Polymerization
Scheme 284. Polymerization of Vinyl Chloride Initiated byBenzoyl Peroxide
The fact that the polymerization was inhibited by TEMPOsupports the radical mechanism. The formation of iodine aminecomplex in the heated solution of 2-cyanopropyl iodide withamine was observed by UV−vis. Also, the deactivation effect ofthe iodine amine complex was confirmed by observation of theNMR of reaction mixture of monomer free radical generated insitu with the iodine amine complex.808
However, considering that amines are good SET donors andreactive for SET dehalogenation of alkyl halides generatingalkyl radical, the mechanism for this reaction can be re-examined and interpreted as a SET process (Scheme 287). The
existence of the radical anion of the monomer or polymerdepends on the stability of the species. The UV−visspectroscopy observation of amine−iodine complex might bethe D−A complex formed when amine was mixed with iodine.This mechanism also explains the observation of visible-light-
induced reversible complexation-mediated LRP of methacry-lates in the presence of amine by the same group.809 Thepolymerization was reported to proceed under irradiation. Nopolymerization was observed in dark. The alkyl radicalgenerated from monomer, amine mixture under irradiationwas trapped by TEMPO and observed by NMR.809
Considering the reports in organic chemistry of amine-mediated SET dehalogenation and cyclization reactions, thevisible-light induced reversible complexation of LRP mightactually follow a SET activation mechanism as in Scheme 287.
3.5.6. LRP Mediated by Amonium Iodides. In 1955, itwas noticed that when MMA was heated with a mixture ofdimethylaniline and benzyl chloride, the polymerization ofMMA happens readily.810 DP of poly(MMA) obtained was1000−2000 in chloroform. The highest DP was obtained whenequal moles of aniline and benzyl chloride were used. Thequaternary ammonium salt was found to be a better catalyst.Hydroquinone inhibits the reaction.810 The reaction exhibitedfree radical mechanism. However, MA, vinyl acetate, and Stywere not polymerized by this method.810 The reaction wasstudied to elucidate the free radical source.788 It was observedthat ammonium from the tertiary aromatic amines is the mostreactive followed by secondary and then primary anilines.N,N,N-Trimethylbenzenaminium showed the highest reactiv-ity.788 The authors concluded that the radical source resultedfrom the decomposition of the quaternary ammonium salts.788
Recently, a LRP mediated with quaternary ammonium salts wasreported.811 High molecular weight polymers with Mn up to140 000 were synthesized. MA, acrylate, styrene, acrylonitrile,and functional MA monomers were polymerized with goodcontrol. Block copolymers were also prepared by thismethod.811 Similar to the amine-mediated LRP, thisammonium-mediated polymerization was also found to havea radical character because the monomer radical could betrapped by TEMPO. No polymerization was observed byheating the monomer alone. Polymerization initiated by AIBNin the presence of iodide was not efficient. The mechanismproposed by the authors is shown in Scheme 288.
The formation of A+I3− was observed by UV−vis. The
deactivation effect of A+I3− was confirmed by 1H NMR. The
generation of polymer radical species is not clear to the authors.Because both amine and iodide are well-established electrondonors in organic chemistry, the activation process is mostprobably a SET process. Alternatively, the iodide can betransferred to A+I− by an atom extraction mechanism (Scheme289).Without additional investigations, it is not possible to
conclude if the activation process in this polymerizationproceeds by SET or AT.
Scheme 285. SET Mechanism Proposed for the Generation of Free Radicals by Amine806
Scheme 286. Reversible Complexation-Mediated LRPa
aReprinted with permission from ref 808. Copyright 2011 AmericanChemical Society.
Scheme 287. SET Mechanism for Activation of LRPMediated by Amine783
Scheme 288. Reversible Activation with QuaternaryAmmonium Salts811
Recent progress in the field of SET-LRP mediated by aminewas achieved by the Haddleton and Percec laboratories.812
They reported an efficient photoinduced SET-LRP method-ology (λmax ≈ 360 nm) for a variety of acrylates, includingbiologically relevant PEG acrylate monomers mediated byaliphatic tertiary amine ligands, such as Me6-TREN, TREN, andPMDETA in the presence of CuIIBr2 (Scheme 290). A slowpolymerization can also be achieved by simply using laboratorylight under similar reaction conditions. In this reaction,irradiation of alkyl halide initiator or the dormant polymer inthe presence of a tertiary amine results in reductivedehalogenation to generate an alkyl radical, the amine radicalcation, and Br− via an OSET mechanism (Scheme 290). ThenLRP is achieved in the presence of an appropriate acrylate.Deactivation of the growing radical is achieved by CuIIBr2/Me6-TREN resulting in dormant polymer chain (Pn-Br) and CuIBr/Me6-TREN, which then regenerate CuII Br2/Me6-TREN viareduction by the amine radical cation and Br− or by thedisproportionation mechanism. Using this methodology, anexcellent degree of control of molecular weight, narrow Mw/Mn
(<1.2), and quantitative retention of polymer chain endfunctionality was achieved. The scope of the reaction wasfurther elaborated via chain extension of the resulting polymerand block copolymerization by sequential monomer addition. Itwas also demonstrated that in the case of photopolymerizationof MA, the reaction is fastest in DMSO (96% conversion, 90min) followed by MeOH (84% conversion), which are bothknown as disproportionating solvents.118,121,436,438 In non-disproportionating solvents, MeCN120 and toluene,436 con-versions remained lower than those obtained with DMSO (67%and 62%, respectively) under similar reaction conditions.
4. OXIDATIVE CHEMISTRY
4.1. MacMillan SOMO Catalysis
In 2000, MacMillan introduced the concept of iminiumcatalysis, which is an enal or enone activation mode thatlowers the energy of the substrate’s LUMO, facilitatingenantioselective C−C and C−N conjugate additions, cyclo-additions, hydrogenations, and Friedel−Crafts alkyla-tions.813,814 Simultaneously, Barbas and List brought to fruitionthe concept of enamine catalysis, which raises the energy ofHOMO in aldehydes and ketones to promote enantioselectiveα-carbonyl functionalization with a large range of electro-philes.815 In 2007, MacMillan’s laboratory demonstrated thatthe enamines and iminium ions rapidly interconvert via a redoxprocess, which can be interrupted by using a SET donor, suchas ceric ammonium nitrate (CAN), to the transient enaminespecies by a SET process, which generates a three-π electronradical cation with a singly occupied molecular orbital (SOMO,Scheme 291).202,816,817
Subsequent addition of π-rich SOMOphiles, such asallylsilanes, to this SOMO activated center results in a highlyselective α-addition product of relatively nonpolar hydrocarbonsubstrates, such as allyl and aryl groups. When chiral SOMO-activated species combine with SOMOphiles, excellent enantiodiscrimination is achieved. In their first report, allylic alkylationof aldehydes was carried out with ceric ammonium nitrate(CAN) as the stoichiometric oxidant and allyltrimethylsilane asthe SOMOphile (Scheme 292).202,816,817
The involvement of the radical cation intermediates wasestablished by the radical-clock experiment.202,818,819 Inaddition, the fact that the electron-deficient olefin ethyl-2-(methyl-trimethylsilyl)acrylate is also an efficient SOMOnucleophile provides evidence for the generation andparticipation of a radical cation species in this reaction.202 Inaddition to the α-substitution of aldehyde and ketones bySOMO catalysis, which occurs via three-π electron radicalcation formation, the MacMillan laboratory also showed thatthe combination of SET by a photoredox catalyst, such asRu(bpy)3, Ir(ppy)3, with organocatalysis can lead to thegeneration of 5π-electron β-enaminyl radical intermediatefrom ketones and aldehydes, which rapidly couple withcyano-substituted aryl rings to result in β-substituted aldehydeand ketone products.820,821 A broad range of aldehydes andketones can be β-functionalized with promising levels ofenantioselectivity. A review published in 2012 on SOMO
Scheme 289. Mechanism of Activation in Ammonium-Mediated LRP811
Scheme 290. Proposed Mechanism for Tertiary-Amine-Mediated, Photoinduced Living Polymerization of Acrylatesa
catalysis is available.822 While in SOMO catalysis, MacMillanused CAN as the oxidant along with nonpolar nucleophilessuch as allylsilanes to prepare α substituted aldehydes orketones, Sibi and Hasegawa reported enantioselective α-oxyamination of aldehydes in the presence of TEMPO usingMacMillan catalyst and a SET reagent, such as FeCl3 orCp2FeBF4 (Scheme 293).823,824 When NaNO2/O2 wasemployed as a cooxidant, a catalytic amount of the SETreagent was enough to result in an excellent yield andselectivity.
4.2. Scholl Reaction
In 1885, Friedel and Crafts reported the coupling reaction ofnaphthalene to produce 2,2-dinaphthyl in 2−3% yield at hightemperature in the presence of AlCl3.
825 However, only 25years later, in 1910 Scholl and Mansfeld developed the field ofaryl−aryl coupling reactions under Friedel−Crafts conditions,which is now known as the Scholl reaction.826 They showedthat quinone 8 can be converted to the π-extended quinone 9by treatment with an excess of neat anhydrous AlCl3 for 45 minat 140−145 °C (Scheme 294).826 Balaban and Nenitzescureformulated the Scholl reaction as “the elimination of two aryl-bound hydrogens accompanied by the formation of an aryl−aryl bond under the influence of Friedel−Craft catalysis”.827,828Although the Scholl reaction is usually carried out in the
presence of a Lewis acid such as FeCl3 or AlCl3, recentlyvarious other oxidants have been shown to positively influencethe reaction, including CuCl2, Cu(OTf)2, MoCl5, SbCl5, etc.,which allows milder reaction conditions.829 The actual
mechanism of the Scholl reaction is debated. Two possiblemechanisms were proposed, that is, involving formation of anarenium cation or a radical cation as intermediate. Themechanism involving arenium cation (Scheme 295) has been
proposed by Baddley,830 which was supported by Nenitzescu,Balaban,827,831 and many other groups. In this mechanism, theσ-complex intermediate or arenium cation is formed, and thegeneration of the cation intermediate is facilitated by thepresence of a protonating agent, for example, HCl. Thishypothesis was supported by the fact that dehydrogenation ofcertain aromatic compounds can occur not only in the presenceof a Lewis acid, like AlCl3, but also with anhydrous HF andPhSO3H, which do not generate radical cations.832
On the other hand, the mechanism involving radical cationintermediate (Scheme 296) was proposed by Rooney and Pink
Scheme 291. Mechanism of Formation of SOMO-Activated Intermediate202,816,817
Scheme 292. SOMO Catalysis202,816,817
Scheme 293. Mechanism of α-Oxyamination Proposed bySibi and Hasegawa823
Scheme 294. Scholl Reaction
Scheme 295. Proposed Mechanism of Scholl Reaction viaArenium Cations832
Scheme 296. Proposed Mechanism of Scholl Reaction viaSET833
in 1961.833 The involvement of the radical cation wasexperimentally supported by the fact that the aromatic radicalcation generated during the Scholl reaction was characterizedby ESR signals.834−836
In another instance, during investigations on the cyclo-dehydrogenation of oligophenylene precursors (C42H30,Scheme 297) that provide the planar corresponding fully
benzenoid product (C42H18), Di Stefano and Negri837
demonstrated a radical cation mechanism pathway by theisolation of the intermediate C42H22, which is part of thestepwise pathway, that is inconsistent with an areniummechanism.837
The cross-coupling of aromatic compounds via the Schollreaction is much more difficult to achieve and less predictableas compared to intermolecular homocoupling or intramolecularcoupling reaction due to poor selectivity of the reaction. Theconditions of this reaction, as well as the starting materials,should be precisely selected to obtain cross-coupling productsin reasonable yields and selectivity. When two starting areneswith different oxidation potentials are reacted under Schollreaction conditions, the oxidation is preferred with the moreelectron-rich component, which further undergoes electrophilicattack to the more electron-rich arene molecule resulting inhomocoupling as the favored reaction over the cross-coupling.832 However, this is overcome when using the propercombination of the principle of steric factors as well as theelectron density of both aromatic molecules.832,838 One of themost important strategy is through a SET mechanism byhypervalent iodine reagent (IIII) demonstrated by Kitalaboratory.832,839 In addition to the intermolecular andintramolecular coupling reaction, the Scholl reaction has beenapplied as a successful tool for the polymerization of substitutedaromatic and heteroaromatic rings. A number of polymerizationreactions under Scholl reaction conditions have been developedby Percec’s laboratory, especially for the synthesis of aromaticpolyethers, which demonstrated the involvement of radicalcation intermediates.840 A detailed discussion on this topic isavailable in the section on “polymer synthesis by Scholl
reaction” (section 4.2.1). It should be noted that especially forScholl oxidation of aryl ethers, it has been long proved that themechanism involves the formation of radical cations.592
4.2.1. Polymer Synthesis by Scholl Reaction. Thediscovery by Kovacic and Kyriakis of oxidative polymerizationof benzene to poly(p-phenylene) in the presence of AlCl3/CuCl2 was the first breakthrough in the application of theScholl reaction for the synthesis of polymers of electron-richaromatic and heteroaromatic compounds (Scheme 298).829,841
It is noteworthy that this reaction was carried out under mildconditions at 25−35 °C and was complete in 2 h. With thisdiscovery, the synthetic applicability of the Scholl reaction forpolyarenes synthesis has significantly broadened, more notablydue to their importance in the dyestuff industry.The mechanism of this reaction continues to be debated.
The involvement of a radical cation intermediate by SET fromthe Lewis acid is one of the most accepted pathways. Kovacic’slaboratory proposed that the benzene radical cation associatesin a coordination manner that is called a stair-step mechanism(Scheme 299).840,842,843 However, Balaban, Nenitzescu,
Clowes, and others829 proposed that more than one mechanismcan be involved depending upon the substrate and conditions,and a detailed review on this topic was reported by Clowsin1968.844 Different proposed mechanisms for Scholl reactionhave been discussed earlier in the section on the Schollreaction. Hence, this section will not repeat the mechanisticaspects of this reaction. Many Lewis acid can be used in thispolymerization, such as FeCl3, MoCl5, SbF5, AsF5, etc. On theother hand, many oxidants, such as MnO2, PbO2, NO2, p-benzoquinone, O2, may be employed for this reaction withAlCl3 as the Lewis acid catalyst.829
The synthesis of electron-rich polyarene and polyheteroar-enes derived from pyrrole, thiophene, indole, and aniline by theScholl reaction is also a well-established field. The synthesis ofthese electron-rich polymers is of great interest due to theirconducting properties, some of them being commercially
Scheme 297. Proposed Mechanism of Scholl Reaction ofOligophenylene837
Scheme 298. Synthesis of Poly(p-phenylene) by the SchollReaction829,841
Scheme 299. Stair-Step Mechanism for Poly(p-phenylene)Synthesis by Scholl Reaction via SET840,842,843
available. Numerous reviews on various aspects of the synthesisand properties of these polymers have been pub-lished.829,832,834,840,845 Although there are controversies aboutthe mechanism involving the synthesis of these polymers, themost commonly accepted mechanism involves radical cationpropagating species. Two possible mechanisms can take placein chain growth step, that is, coupling between two radicalcations (Scheme 300, a) or coupling between a radical cationand a neutral species (Scheme 300, b).840,846,847 Recent studiessuggest the radical−substrate coupling is responsible for thedimerization reaction.848
The synthesis of aromatic polyethers and polyarylenesincluding poly(ether sulfone)s and poly(ether ketone)s bythe Scholl reaction is a topic of great interest. Bilow and Millerhave applied Kovacic’s polymerization method to preparebranched soluble polyphenylenes.849 They showed that thecationic oxidative polymerization of m-terphenyl, o-terphenyl-1,3,5-triphenylbenzene, or mixtures of the terphenyls withbiphenyl and with benzene can be accomplished with molecularweight of polymer reaching up to 3000 in the molten stateusing AlCl3/CuCl2 or FeCl3.
849 Remarkably, in 1973 R. G.Feasey850 described the polycondensation of di-1-naphthoxyalkanes to form linear, high molecular weight poly(dinaphthylalkylene ether)s using anhydrous FeCl3 at room temperature(Scheme 301)
Following this publication, the synthesis of aromaticpolyethers as well as polyarylenes under mild reactioncondition was reported from Percec’s laboratory.840,851
To understand the impact of monomer structure on thepolymer syntheses by Scholl reaction, it is important to examinethe correlation between the structure of the monomers to theproperties of the polymers. Two factors impact the polymer-izability of the monomer: the oxidative potential of themonomer and the stability of the resulting radical cation.851
An example discussed in the literature is the comparison of thepolymerization of 4,4′-di(1-naphthoxy)diphenyl sulfone (M1)and that of 1,5-di(1-naphthoxy)pentane (M2). Both werecarried out in nitrobenzene at room temperature in the
presence of FeCl3 (Scheme 302).852 The oxidation of M1 ismore difficult than the oxidation of M2 because M1 has an
electron-deficient diphenylsulfone group between two naph-thoxy groups. Hence, the initial one-electron oxidation of M1 isslower than M2. However, the resulting radical cation from M1is more reactive. These two factors should be considered in thepolymerization.The 4 position of the monomer is the most electron-rich
position of the naphthyl ring, and hence will be oxidized first. Inthe polymerization process, M1 polymerized at a higher ratethan M2 and produced polymers with higher number-averagemolecular weight. This can be explained by the reactivity ofradical cation intermediates generated for both monomer units.The radical cation generated from M1 (R1) is more reactivethan radical cation generated from M2 (R2) because the latteris more stabilized by the resonance effect (Scheme 303).852
Soluble unsubstituted polyarenes, containing alternatingbinaphylene and biphenylene units, in addition to bis(phenoxy)and bis(phenylthio) alkane, bis(2-naphthyloxy) sulfone, bis-(phenoxy) sulfone, and bis(phenylthio) sulfone, were synthe-sized by Scholl reaction conditions.840 The monomers used andproperties of resulting aromatic polyethers are summarized inScheme 304.The references for polymerization of each monomer are
given here: M1, M2,853 M3,854 M4,855 M5, M6, M7,856 M8,M8′, M8″, M9,857 M10,858 M11,859 M12,860 and M13.861 M7and M8 were prepared by the reduction of M2 and M5.
Scheme 300. Proposed Mechanisms of Polypyrrole Synthesisby the Scholl Reaction840,846,847
Scheme 301. Synthesis of Poly(dinaphthyl alkylene ether)sby the Scholl Reaction850
Scheme 302. Polymerization of 4,4′-Di(1-naphthoxy)diphenyl Sulfone and 1,5-Di(1-naphthoxy)pentane by the Scholl Reaction852
Scheme 303. Radical Cation Intermediates of M1 and M2852
Besides aromatic polyethers, polyarenes can also besynthesized by the Scholl reaction, as demonstrated by Percec’slaboratory (Scheme 305).862
The polyarenes synthesized by the Scholl reaction weresummarized in Scheme 305. Interestingly, the intramolecularScholl reaction was observed (Scheme 306).862 The structureformed after the intramolecular Scholl reaction is similar to therecently reported graphene structures synthesized on surface bythe Scholl reaction.863
Besides the application of the Scholl reaction in the synthesesof aromatic polyethers, the application of the Scholl reaction in
graphene syntheses has attracted considerable attention.864
Graphenes can be synthesized by dehydrogenation frompolyaromatic precursors in both solution and on surfaces.582
Recently, Mullen laboratory developed a procedure to convertstilbenoids to large polycyclic aromatic networks using a [2 +2] cycloaddition followed by the Scholl reaction (Scheme307).834,863,865 Using this strategy, they have reported thesynthesis of large two-dimensional graphene-like nanorib-bons.863,864,866 The mechanisms of these reaction have beeninvestigated by the same group, and it was demonstrated thatthe reaction produces isolable intermediates, which support the
Scheme 304. Summary of Monomers Employed in the Synthesis of Aromatic Polyethers by the Scholl Reaction at 25 °C
hypothesis of the involvement of a radical cation intermediateinstead of formation of an arenium cation intermedi-ate.837,863,864,866
The syntheses of graphenes in solution and on surfaces werereviewed until September 2012.864,867 Progress after that will behighlighted hereinafter.A 26-ring C80H30 nanographene that displaces a distorted,
nonplanar structure was recently synthesized via the Scholl
reaction and by other methods.868 The chemical syntheses aredisplaced in Figure 12.The ability of forming five strained seven-member rings in
one step demonstrated the synthetic ability of the Schollreaction in polymer synthesis and in supramolecular chemistry.
4.2.2. Living Anionic Polymerization of StyreneInitiated by Electron Transfer. Living anionic polymer-ization was demonstrated by the Szwarc laboratory in1956.170,364,869 The foundation of this discovery can be tracedback to 1910,870,871 when several reports were publishedshowing that a viscous material is generated from dienes in thepresence of alkali metals. In 1929, Karl Ziegler explained theoutcome of the addition reaction of sodium or lithium metalswith dienes and proposed that two atoms of sodium add to theunsaturated double bonds of diene, which forms two C−Nabonds. He also proposed a mechanism for the formation ofviscous material through propagation via insertion of monomerinto the C−Na bond by anionic polymerization.872 However, itwas Michael Szwarc873 who first demonstrated the livinganionic polymerization of Sty using sodium naphthalenide intetrahydrofuran (THF). He suggested that the initiation occursvia SET from the sodium naphthalenide radical anion to Stymonomer.170,364,869 A new species, a styryl radical anion, formsupon transfer of an electron from the sodium naphthalenide(Scheme 308). Many aromatic compounds in the presence ofalkali metals in polar solvents form radical anions through ETto an electron-deficient aromatic hydrocarbon or monomer,which can be used as initiators in anionic polymerization. Inaddition, many olefins containing aromatic substitution canreact with alkali metals to form radical anions. For example,diphenylethene (DPE) reacts with sodium metal to generate aradical anion in a polar solvent. Similarly, the reaction ofsodium with σ-methylSty yields a radical anion in polarsolvents. The general mechanism of the formation of thesetypes of initiators is an OSET process from the surface of thealkali metal. The ET takes place during the solvation of metalsin polar solvents such as THF, glymes, ether, and liquidammonia.874
5. REACTIONS INVOLVING BOTH REDUCTIVE ANDOXIDATION CHEMISTRY
5.1. Organic Electrosynthesis
Electrochemistry has been known as a valuable tool in organicsynthesis for a long time. The first organic electrosynthesis wascarried out by Faraday in 1834 when he demonstrated thegeneration of ethane from the anodic oxidation of aqueousacetate solutions. This reaction was later studied in detail byKolbe149 who performed the synthesis of dimeric alkanes usingorganic acid carboxylates as starting materials. This is nowknown as the Kolbe reaction (Scheme 309). The first cathodicreduction of an organic compound seems to be the reductivedehalogenation of trichloromethanesulfonic acid to methane-sulfonic acid by a zinc electrode.875,876
In recent years, organic electrosynthesis has become animportant field in organic synthesis including for the synthesisof natural products and for the commercial electroorganicprocesses. In a comprehensive review, Sequeira and Santos877
reported electrochemical routes for industrial synthesis andprovided a list with 56 examples of industrial organicelectrosynthesis processes in ongoing time. There are a numberof comprehensive reviews available, including several recentthat cover many of these aspects in great details.876,878−883
Scheme 305. Polyarenes Synthesized by the SchollReaction862
Hence, we will attempt to discuss this topic only briefly. Formore details, the readers are referred to these reviews.It is needless to say that the primary reaction in any
electrosynthesis is the SET process. During an electrochemicalreaction, SET takes place from cathode to molecule’s LUMOposition to generate a radical anion or from molecule’s HOMOto anode to generate a radical cation. After the formation ofhighly active radical cations and radical anions on the surface ofthe electrode, they diffuse into the solution. These radical ionscan further undergo fragmentation to radicals, which may befurther reduced or oxidized to generate anions and cations.These reactive species undergo various important reactionssuch as C−C bond formation via dimerization, cyclization orrearrangement reactions, polymerization of electron-richaromatic or heteroaromatic compounds (Scheme310a),881c,884 and aromatic substitution (Scheme 310b).885
However, reactions of these intermediates produced directlyat the electrode by heterogeneous SET can result in inhibitionof the electrode reaction by formation of nonconducting films.This situation can be overcome by using a mediator, which is anelectro generated reagent that diffuses into the bulk solutionwhere it is capable of SET to the target substrate.881c Animportant advancement in the modern organic electrosynthesisprocesses that involves the use of electro auxiliary is noteworthy(Scheme 311). This allows the SET process selectively at theposition needed for a subsequent chemical process. Acomprehensive review on this topic is available.881b
Another major recent development in the area of electro-synthesis is the switch to ionic liquids as a more ecological andeasily recyclable solvent.886−889 The common organic solventshave several disadvantages, such as low dielectric constantvolatility and flammability. Because water is not a good choiceeither due to the insolubility problem for most of the organiccompounds, the use of ionic liquid has great advantages such ashigh ionic conductivity, nonvolatility, and low flammability. Forinstance, the selective fluorination of organic compound is not
straightforward, and very often requires hazardous reagents.Selective anodic fluorination seems to be an ideal methodbecause it can be carried out under mild conditions.877 Thefluorination is usually conducted in aprotic solvents containingHF salt ionic liquids such as Et3N·3HF and Et4NF·3HF. Forinstance, Meurs and his co-workers567 used an Et3N·3HF ionicliquid as both a solvent and a supporting electrolyte and also asthe fluorine source for the anodic fluorination of benzenes,naphthalene, olefins, furan, benzofuran, and phenanthroline(Scheme 312).
5.2. SET of Enolates
The ability of enolate anions to transfer a single electron tovarious organic substrates has been known for a longtime.890−892 For example, the Ashby laboratory reported thatthe aldol condensation reactions involving enolate nucleophileswith aromatic ketones proceed by a SET mechanism. Thegeneration of radical species was determined by ESRspectroscopy (Scheme 313).893 They have also demonstratedthe involvement of a SET process in the reaction of a lithiumenolate with a primary alkyl iodide.894 A comprehensive reviewon this topic published in 1988 is available.22
Oxidative coupling of enolates resulting in C−C bondformation has emerged as an important tool in organicsynthesis. This reaction was first reported in 1935 by Ivanoffand Spassoff.895 They demonstrated that when magnesiumchloride enolate, generated from the reaction of sodiumphenylacetate and Grignard reagent, is treated with Br2, thehomocoupled dimers are produced in 22% yield. Several yearslater in 1968, Kauffmann reported the first example of theoxidative dimerization of a ketone enolate using CuI salts.896,897
In the same year, Rathke reported the oxidative dimerization ofester enolates using soluble copperII as oxidant in moderate toexcellent yields.898 Meanwhile, many other oxidants have beenreported to mediate the coupling, such as various copper andiron salts, titanium salts, silver salts, N-iodosuccinimide, I2,hypervalent iodine-based reagents, potassium permanganate,
Scheme 307. Synthesis of Graphene-like Nanoribbonsa
direct electrochemical oxidation, short chain alkyl polyhalides,etc.899−901 In their seminal publication, Ivanoff and Spassoffproposed that the formation of a radical intermediate isresponsible for the coupling reaction.895 However, the actualmechanism of these reactions is still under debate, although theformation of a radical cation by SET to the oxidant is the most
widely accepted mechanism. For instance, Renaud and Fox
showed that the mechanism for oxidative dimerization of
carboxylic acid dianions involves SET to iodine, producing a
radical anion. Their proposed mechanism is shown in Scheme
314.902
Figure 12. (a) Important features of the grossly warped C80H30 nanographene. (b) Synthetic routes to C80H30 (4) and its deca-t-butyl derivativeC120H110 (8) from corannulene (1). For route 1, direct 5-fold C−H biphenylation, the reaction conditions were (i) tris(o-biphenylyl)boroxin (2.0equiv), Pd(OAc)2 (20 mol %), o-chloranil (5.0 equiv), DCE, 80 °C, 16 h and (ii) DDQ (10 equiv), trifluoromethanesulfonic acid (TfOH)/CH2Cl2(5:95), 0 °C, 30 min. For route 2, stepwise 5-fold C−H borylation−arylation, the reaction conditions were (iii) (Ir(OMe)(cod))2 (20 mol %),B2(pin)2 (5.2 equiv), 4,4′-dimethylbipyridyl (40 mol %), potassium t-butoxide (10 mol %), tetrahydrofuran (THF), 85 °C, 4 days, (iv) 2-bromobiphenyl (20 equiv), Pd2(dba)3·CHCl3 (10 mol %), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 20 mol %), Cs2CO3 (10equiv), toluene/water (2:1), 80 °C, 24 h, and (v) DDQ (10 equiv), TfOH/CH2Cl2 (5:95), 0 °C, 30 min. For route 3, direct 10-fold “total” C−Hphenylation, the reaction conditions were (vi) tris(p-(t-butyl)phenyl)boroxin, Pd(OAc)2, o-chloranil, DCE, 80 °C, repeat for 3−4 cycles and (vii)FeCl3 (31 equiv), CH2Cl2/nitromethane (115:1), 25 °C, 1 h. cod, 1,5-cyclooctadiene; pin, pinacol; dba, dibenzylideneacetone; cat., catalyst; DCE,1,2-dichloroethane; DDQ, 2,3-dichloro-5,6-dicyanobenzoquinone. Reprinted by permission from ref 868. Copyright 2013 Macmillan Publishers Ltd.
Although the numerous effective oxidizing agents open anexcellent methodology for C−C bond formation via oxidativehomocoupling of enolate of ketone, carboxylic acid, or ester,examples of intermolecular oxidative heterocouplings ofunfunctionalized carbonyl enolates are still limited.903 In thiscontext, Saegusa and co-workers were the first to demonstrate
that the heterocoupling of enolates is possible by using at least a3-fold excess of one of the monomers.904,905 Similarly, Itoh andco-workers demonstrated cross-coupling of two differentenolates of esters by electrolytic methods using a 3-fold excessof one enolate to achieve the selectivity of cross-coupling overhomocoupling.906 Baran and co-workers demonstrated the firstbreakthrough of cross-coupling of lithium enolates with a
Scheme 308. Mechanism of Living Anionic Polymerization of Sty Initiated by Outer-Sphere170,364,869
Scheme 309. Mechanism of the Kolbe Reaction149
Scheme 310. Mechanism of (a) Polymerization by AnodicOxidation and (b) Aromatic Substitution by AnodicOxidation881c,884,885
Scheme 311. Electrolysis in the Presence of ElectroAuxiliary881b
Scheme 312. Organo-fluorination by Electrochemistry567
Scheme 313. Proposed Mechanism of Aldol Condensationvia SET893
Scheme 314. Coupling Reaction of Acid via Enolization902
satisfactory yield.907 Their mechanistic study revealed twopossible pathways for this reaction, that is, involving an anionicor a radical anion. The involvement of a radical anion pathwaythrough SET mechanism is more evident.903 In subsequentwork, Flowers and Casey,908 given the mechanistic details ofthis selectivity, showed that the selective generation of cross-coupled products for the ketones resulted due to hetero-aggregation of the lithium enolates.903
5.2.1. Asymmetric and Symmetric Oxidative Couplingof Enols and Phenols Temporarily in an IntramolecularStructure. Another advancement in the cross-couplingreaction of enolates was brought by Schmittel’s laboratory. In1998, Schmittel and co-workers909 reported that in thepresence of ceric ammonium nitrate (CAN), silyl bisenolethers undergo intramolecular oxidative coupling (Scheme315).
A high level of diastereocontrol was achieved. Bisnaphtholwith various substituents was synthesized. They also showedthat without intramolecularization the oxidative SET dimeriza-tion of enol derivatives proceeds without any diastereoselectiv-ity.910−912 In addition, the use of Fuson-type metal enolatesgive rise to only the M−O bond cleavage, which prevents thedimerization of two enol radical ions due to steric hindranceand produces substituted benzofuran as product (Scheme316).910,912
6. SET IN THE FORMATION AND CLEAVAGE OFPROTECTIVE GROUPS
SET in protection/deprotection methodology is a veryimportant field developed and summarized in numerousbooks and reviews.913 Only some representative examples ofSET reactions in the formation and cleavage of protectivegroups are provided.Solvated electrons are used to cleave benzyl ether groups
(Scheme 317) under mild conditions when the other functionalgroups in the molecule tolerate these conditions.914
Becker introduced dichlorodicyanobenzoquinone (DDQ) inthe oxidation of phenols. Today, DDQ is used in selectivecleavage of p-methoxy benzyl ethers (PMB) in the presence ofother hydroxyl protecting groups.913d Becker originallyproposed a two-electron transfer mechanism to account forthe oxidation of phenols by DDQ.915 A more detailedmechanistic study showed that SET within a π-complex actuallyaccounts for the oxidation.916 A dark colored CTC wasobserved during the cleavage of PMB by DDQ (Scheme318).917
Other than reduction methods, oxidative chemistry via SETis also used in the cleavage of protective groups.913d O-, N-Tr,MMTr, and DMTr groups from nucleosides and nucleotidesare cleaved efficiently and selectively by catalytic amounts of
ceric ammonium nitrate (CAN) supported on silica gel. Thereaction and the SET mechanism accounting for the catalyticnature of the CAN are provided in Scheme 319.918
7. CONCLUDING REMARKSAs Marcus stated in his Nobel Prize lecture in 1992,3 “the fieldof electron transfer processes has grown enormously, both inthe field of chemistry and biology.” This field has emerged intomany specialized areas in organic, inorganic, materials,supramolecular, and polymer chemistry. The understandingof SET processes evolved greatly due to the contributions ofMulliken,14b Taube,2c Marcus,3 Huber,18 Eberson,919 Cha-non,19b Kochi,15 Ashby,22 Pross,21 Saveant,26 Evans,920 andmany other. The mechanisms of some traditional reactionsfrom organic chemistry have been re-examined and explainedby SET-mediated pathways. Most notable are the SRN1mechanism100 and the Grignard reaction.22 New syntheticmethods developed on the basis of SET mechanisms involvethe SmI2 chemistry
223,921 and the more recent base-promotedhomolytic aromatic substitution reaction.749 SET reactionsoccurring spontaneously, being promoted by heat or radiation,or at the electrodes have been discussed in this Review both
from the mechanistic and from the synthetic perspectives.Generation of radical ions and radical intermediates and thereactivity patterns of these odd electron species have led tochemical developments that are different from the moretraditional two-electron processes. Progress of SET in polymersynthesis has developed in parallel with the progress of SET inorganic synthesis. In some fields such as radical reactions basedon homolytic processes, for technological reasons, polymersynthesis by radical reactions, as well as mechanistic andreactivity studies of radicals, were originally more advanced inpolymer synthesis than in organic chemistry. As discussed in arecent review on SET-LRP,8 the advancement of organicchemistry promotes the progress of polymer chemistry, andvice versa. SET theories, methodologies, and reactions have alsoimpacted the field of material chemistry in areas such aselectronic materials, solar energy conversion, nano devices atinterfaces, batteries, and corrosion, to name just a few. Theimpact of SET in understanding biological phenomena such asrespiration, photosynthesis, the light emission by fireflies, andmany others is unvaluable.4b However, questions andchallenges still exist in SET-mediated chemistry. Clarifyingexisting mechanisms including the concerted and stepwise SET-mediated reductive dehalogenation of aromatic and aliphatichalides and of other halogenated species is important for bothtechnologic and environmental purposes. The design of novelsynthetic routes to functional molecules, macromolecules, andsupramolecular assemblies by SET rather than thermal-mediated homolysis is expected to provide energy efficientprocesses inspired by biological systems. This Reviewattempted to provide a compact but comprehensive discussionof old, never reviewed, almost forgotten, and new SETmethodologies and mechanisms employed in organic, materials,and macromolecular synthesis as well as in the synthesis offunctional building blocks relevant for supramolecular chem-istry.
The authors declare no competing financial interest.
Biographies
Na Zhang was born in Jiangxi Province, China. She received her B.S. inchemistry from the University of Science and Technology of China in2009, where she worked on a mechanistic study of oxidation of CO ongold nanoparticles supported on SiO2/Fe2O3 and was awarded theOutstanding Undergraduate Research Award. In the same year, shejoined the Ph.D. Program from the Department of Chemistry at theUniversity of Pennsylvania, and since 2010 she has worked in thelaboratory of Professor Virgil Percec toward her Ph.D. Her researchinterests include the development of Ni-catalyzed borylation andcross-coupling reactions, the design of new nickel-based catalysts, andthe application of transition-metal catalysts in the synthesis of organicand macromolecular compounds.
Shampa R. Samanta was born in Kolkata, India. She received her B.Sc.degree (Hon) in chemistry from Calcutta University, Kolkata in 2005and a M.Sc. degree in organic chemistry from the Indian Institute ofTechnology, Roorkee in 2007. In the same year, she joined theUniversity of Miami for her Ph.D. studies and worked in the field onsupramolecular photochemistry under the supervision of Professor V.Ramamurthy. Her research work was focused on controllingphotochemical and photophysical behavior of organic photoresponsiveguest molecules by the confined nature of the macromolecular hosts,such as mimicking the excited-state behavior of GFP chromophore,controlling the excited-state geometric isomerization of olefins, and thetriplet−triplet energy transfer process between an encapsulated donor/acceptor in aqueous medium and on the surface of gold nanoparticles.In 2013 she joined the group of Professor Virgil Percec at theUniversity of Pennsylvania in a postdoctoral position. Her researchinterests include synthetic organic chemistry, macromolecular, andsupramolecular chemistry.
Brad Rosen was born in Philadelphia, PA. He received his A.B. andA.M. in Chemistry from Harvard University in 2005. In 2009, hereceived his Ph.D. from the University of Pennsylvania under thedirection of Professor Virgil Percec. His doctoral studies focused onthe development of Ni-catalyzed cross-coupling and borylation,synthesis and retrostructural analysis of self-assembling dendrons,origins, transfer, and amplification of chirality at the supramolecularlevel, and the elaboration of single electron transfer living radicalpolymerization. He was the recipient of a Rohm and Haas GraduateResearch Fellowship, an NSF Graduate Research Fellowship (2005−2008), an ACS Division of Organic Chemistry Graduate Fellowship(2008−2009, sponsored by Roche, Inc.), a University of PennsylvaniaDissertation Fellowship (2009), and the 2010 Miller Award for thebest Doctoral Thesis from the Department of Chemistry at theUniversity of Pennsylvania. Brad joined DuPont Central Research andDevelopment in 2009 and is presently a New Product DevelopmentLeader in DuPont’s Titanium Technologies Business.
Virgil Percec was born and educated in Romania (Ph.D., 1976). Hedefected from his native country in 1981, and after short postdoctoralappointments at the Universities of Freiburg, Germany, and Akron, hejoined the Department of Macromolecular Science at Case WesternReserve University in Cleveland (1982) as an Assistant Professor. Hewas promoted to Associate Professor in 1984, to Professor in 1986,and to Leonard Case Jr. Chair in 1993. In 1999 he moved to theUniversity of Pennsylvania as a P. Roy Vagelos Professor of Chemistry.Percec’s research interests are at the interface between organic,bioorganic, supramolecular, polymer chemistry, and liquid crystals,where he contributed 690 refereed publications, 60 patents, over 1100endowed and invited lectures, and edited 17 books. His list of awardsincludes Honorary Foreign Member to the Romanian Academy(1993), Humboldt Award for Senior U.S. Scientists (1997 and 2012),NSF Research Award for Creativity in Research (1990, 1995, 2000),PTN Polymer Award from The Netherlands (2002), the ACS Award
in Polymer Chemistry (2004), the Staudinger−Durrer Medal fromETH (2005), the International Award of the Society of PolymerScience from Japan (2007), Doctor Honoris Causa from Universitiesof Iasi, Romania and Athens, Greece (2007), the H. F. Mark Medalfrom the Austrian Research Institute for Chemistry and Technology(2008), Honorary member of the Israel Society of Chemistry (2009),the Inaugural ACS-Kavli Foundation Innovation in Chemistry Lectureand Award (2011), Honorary Professor of the Australian Institute forBioengineering and Nanoscience (2012), and Foreign Member of theRoyal Swedish Academy of Engineering Sciences (2013). He serves onthe Editorial Boards of 21 international journals.
ACKNOWLEDGMENTS
Financial support by the National Science Foundation (grantsDMR-1066116 and DMR-1120901), the Humboldt Founda-tion, and the P. Roy Vagelos Chair at the University ofPennsylvania is gratefully acknowledged.
DP degree of polymerizationDPE diphenylethenedr diastereomeric ratioDT degenerative transferDTC sodium diethylcarbamodithioateEA ethyl acrylateEC ethylene carbonateEDA electron donor−acceptorEDG electron-donating groupee enantiomeric excesser enantiomeric ratioESR electron spin resonanceET electron transferETC electron transfer catalyst or electron transfer
catalysisEWG electron-withdrawing groupGPC gel permeation chromatographyGT group transferHDA donor−acceptor interaction energyHEA 2-hydroxyethyl acrylateHEMA (hydroxyethyl)methacrylateHFIP 1,1,1,3,3,3-hexafluoro-2-propanolHMPA hexamethylphosphoramideHOMO highest occupied molecular orbitalIBX 2-iodoxybenzoic acidIn initiatorinterfer initiator-transfer agent-terminatorISET inner-sphere electron transferIUPAC International Union of Pure and Applied
Chemistrykact rate constant of activationKATRP equilibrium constant of ATRPkdeact rate constant of deactivationKdis equilibrium constant of disproportionationkp rate constant of polymerizationkt rate constant of bimolecular terminationLRP living radical polymerizationLUMO lowest occupied molecular orbitalMA methyl acrylateMALDI-TOF matrix-assisted laser desorpton/ionization-time-
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