inorganics Review ReviewFerrocenyl Migrations and Molecular FerrocenylRearrangements: Migrations The Significance and Molecular of Electronic Rearrangements: The Significance of Electronic Charge Delocalization Michael J. McGlinchey Michael J. McGlinchey School of Chemistry, University College Dublin, D04 V1W8, Belfield, Dublin 4, Ireland; School of Chemistry, University College Dublin, D04 V1W8 Belfield, Dublin 4, Ireland; [email protected] [email protected]

Received: 27 November 2020; Accepted: 9 December 2020; Published: 11 December 2020


Received: 27 November 2020; Accepted: 9 December 2020; Published: 11 December 2020
 Abstract: The enhanced stabilization of a carbocationic site adjacent to a ferrocenyl moiety was Abstract:recognizedThe within enhanced a few stabilization years of the of a discovery carbocationic of sandwich site adjacent compounds. to a ferrocenyl While moiety a detailed was recognizedunderstanding within of a the few phenomenon years of the discovery was the of subject sandwich of compounds.some early debate, While a detailed researchers understanding soon took ofadvantage the phenomenon of it to control was the the subject ease ofand some direction early debate, of a wide researchers range of soon molecular took advantage rearrangements. of it to control We, thehere ease, discuss and direction the progress of a wide in this range area of molecularfrom the pioneering rearrangements. studiesWe, of here, the discuss 1960s, to the more progress recent in thisapplications area from in the chromatography pioneering studies and of analytical the 1960s, detection to more recenttechniques, applications and currently in chromatography in the realm and of analyticalbioactive organometallic detection techniques, complexes. and Several currently classic in the reactions realm of inv bioactiveolving ferrocenyl organometallic migrations, complexes. such Severalas the pinacol, classic reactions Wolff, Beckmann, involving ferrocenyland Curtius, migrations, are discussed, such as as the well pinacol, as the Wol influenceff, Beckmann, of the andferrocenyl Curtius, substituent are discussed, on the as wellmechanisms as the influence of the Nazarov, of the ferrocenyl Meyer-Schuster, substituent benzoin on the, mechanismsand Stevens ofrearrangements. the Nazarov, The Meyer-Schuster, preparation anbenzoin,d isomerizations and Stevens of ferrocenyl rearrangements.-stabilized The vinyl preparation cations and isomerizationsvinylcyclopropenes, of ferrocenyl-stabilized together with the vinyl specific cations cyclization and vinylcyclopropenes, of acetylcyclopenta togetherdienyl with-metal the specificderivatives cyclization to form of1,3,5 acetylcyclopentadienyl-metal-substituted benzenes, demonstrate derivatives the to versatility form 1,3,5-substituted and generality benzenes, of this demonstrateapproach. the versatility and generality of this approach.

Keywords: metalmetal-stabilized-stabilized carbocations; reaction mechanisms; NMR; bioorganometallics

1. Introduction The ability ability of of the the ferrocenyl ferrocenyl moiety moiety to tostabilize stabilize an adjacent an adjacent carbocationic carbocationic cente centerr has long has been long beenattributed attributed to delocalization to delocalization of the of the electron electron deficie deficiencyncy onto onto the the iron iron atom atom [1] [1.]. The The X-rayX-ray crystallographically established [2,3] [2,3] tendency of of the cationic α--carboncarbon atom to lean towards the metal as in 1, was originally interpreted inin terms of an overlap of the vacant 2p orbital on carbon with a filled filled 3 3dd orborbitalital of of suitable suitable symmetry symmetry on on iron iron [4] [4. Taking]. Taking a more a more extreme extreme view, view, one one could could regard regard the + thesystem system as a asneutral a neutral fulvene fulvene ligand ligand coordinated coordinated to a to [(C a5 [(CH5)Fe]5H5+)Fe] unit,unit, as depicted as depicted in 2 (Figure in 2 (Figure 1), but1), butthis thishas been has been criticized criticized based based on the on low the barrier low barrier to rotation to rotation about about the exocyclic the exocyclic bond bondin some in somecases cases[5,6]. [5,6].

+ R R Fe R +Fe R

1 2 Figure 1. Delocalization of charge from the cationic α carbon onto the iron atom.

Fortunately, a comprehensive overview of this, sometimes controversial, phenomenon has been presented by Gleiter, Bleiholder, and Rominger [7]. Nevertheless, it is this character of charge Inorganics 2020, 8, x; doi: FOR PEER REVIEW www.mdpi.com/journal/inorganics

Inorganics 2020, 8, 68; doi:10.3390/inorganics8120068 www.mdpi.com/journal/inorganics Inorganics 2020, 8, x FOR PEER REVIEW 2 of 22 Inorganics 2020, 8, x FOR PEER REVIEW 2 of 22

Inorganics 2020, 8, 68 2 of 23 Fortunately, a comprehensive overview of this, sometimes controversial, phenomenon has been presented by Gleiter, Bleiholder, and Rominger [7]. Nevertheless, it is this character of charge delocalization that facilitates a number of molecular rearrangements or ferrocenyl migrations, as we delocalization that facilitates a number of molecular rearrangementsrearrangements or ferrocenyl migrations, as we shall attempt to demonstrate. shall attempt to demonstrate.

2. Ferrocenyl Ferrocenyl-Mediated-Mediated Carbocationic Rearrangements

2.1. Isomerizations of Secondary to Tertiary CarbocationsCarbocations Following pioneering studies by Cais [[8]8],, dissolution of ferrocenylferrocenyl-substituted-substituted alcoholsalcohols in 1 1 trifluoroacetic acid acid allowed allowed the the acquisition acquisition of well-resolved of well-resolvedH NMR 1H NMR spectra spectra by several by several other groupsother groups [9–11], and[9–11] revealed, and revealed the unusual the unusual stability stability of the of carbocations the carbocations so generated. so generated.Subsequently, Subsequently, in a in series a series of ground-breakingof ground-breaking papers, papers, Watts Watts and and his his group group reported reported the the rearrangement rearrangement behavior behavior of aof number a number of alkylferrocenylof alkylferrocenyl carbocations carbocations upon upon protonation protonation of theirof their precursor precursor alcohols alcohols [12 ].[12]. Typically, thethe quantitativequantitative conversionconversion ofof thethe ferrocenyl-stabilizedferrocenyl-stabilized secondary carbocationcarbocation 3 intointo itsits tertiary isomer isomer 44, ,is is in in accord accord with with the the accepted accepted hierarchy hierarchy of stable of stable carbocations. carbocations. At first At firstsight, sight, this thisappears appears to be to a be double a double shift shift rearrangement rearrangement whereby whereby an an alkyl alkyl migration migration to to form form the ββ-ferrocenyl-ferrocenyl cation 5 isis followedfollowed byby aa [[11,2,2]-hydrogen]-hydrogen shiftshift toto yieldyield thethe observedobserved product.product. However, thethe authorsauthors did not prefer this mechanism since the intermediate rearrangement product, 5, would undoubtedly be thermodynamically disfavored relative to the ferrocenyl-stabilizedferrocenyl-stabilized startingstarting cation 33.. Instead, they proposed that the initialinitial methylmethyl migrationmigration might proceed synchronously with the formation of a short-livedshort-lived spirospiro-diene-diene species species6 (depicted 6 (depicted in Scheme in Scheme1) which 1) could which reopen could with reopen concomitant with concomitant hydrogen migration,hydrogen migration, thus generating thus thegenerating observed the final observed product fin [13al]. product In such a[13] scenario,. In such the a cationicscenario, charge the cationic would charge would be delocalized onto the metal in the transition state. The analogous rearrangement of+ becharge delocalized would be onto delocalized the metal inonto the the transition metal in state. the transition The analogous state. rearrangement The analogous of rearrangement [Fc–CH–CPh3 ]of, [Fc–CH–CPh3]+, 7, into + [Fc–CPh–CHPh2]+, 8, was also observed (Scheme 2), but in this case the 7[Fc, into–CH [Fc–CPh–CHPh–CPh3]+, 7, into2] [Fc, 8,– wasCPh also–CHPh observed2]+, 8, was (Scheme also2 ), observed but in this (Scheme case the 2), doubly-benzylic but in this case cation the doubly-benzylic cation+ [Fc–CHPh–CPh2]+, 9, might be a viable intermediate [14]. [Fc–CHPh–CPhdoubly-benzylic2 ]cation, 9, might [Fc–CHPh be a viable–CPh2 intermediate]+, 9, might be [ 14a viable]. intermediate [14]. Me Me Me Me Me Me Me Me OHMe + Me OH CF3CO2H + Fe H 3 2 Fe Me H Fe H Fe H Me H 3 Me + Fe Me + Fe Me Me 6 Me Me H 6 + H Me Me MeMe Me Me + Fe H Fe H Fe Me 5 4 5 4 Scheme 1. Rearrangement of 2° to 3° ferrocenyl trimethyl-carbocations. Scheme 1. Rearrangement of 22°◦ to 3° 3◦ ferrocenyl trimethyl trimethyl-carbocations.-carbocations. Ph Ph Ph Ph Ph Ph Ph + Ph H Ph + H Ph Ph Ph + Ph Ph Fe Ph + Fe H Fe H Fe H Fe Ph 7 9 8

SchemeScheme 2.2. Rearrangement of 22° to 33° ferrocenyl tri triphenyl-carbocations.phenyl-carbocations. Scheme 2. Rearrangement of 2°◦ to 3°◦ ferrocenyl triphenyl-carbocations. 2.2. Rearrangements of Vinyl and Allyl Cations 2.2. Rearrangements of Vinyl and Allyl Cations This work was elegantly extended to include the addition reactions of trityl cations to alkynylferrocenesThis work was to generate elegantly ferrocenyl-stabilized extended to include vinyl the carbocations, addition reactions10, that underwent of trityl cyclization cations to alkynylferrocenes to generate ferrocenyl-stabilized vinyl carbocations, 10, that underwent cyclization

Inorganics 2020, 8, 68 3 of 23 InorganicsInorganics 20 202020, ,8 8, ,x x FOR FOR PEER PEER REVIEW REVIEW 33 of of 22 22 tototo form form form indenes, indenes, 1111 [15][[15]15]... The The The thermodynamic thermodynamic thermodynamic driving driving driving force force force in in in each each case case is is the the positioning positioning positioning of of a a a carbocationiccarbocationiccarbocationic site site adjacent adjacent to to the the ferrocenyl ferrocenyl moiety,moiety, asasas shownshownshown ininin SchemeSchemeScheme3 3..3.

AArr ++

+ AArr AArr ++ + RR AArr33CC FFee FFee RR FFee AArr 1100 RR --HH++

HH++

++ AArr --HH AArr ++ Ar AArr FFee Ar FFee RR HH RR 1111 SchemeScheme 3. 3. IndeneIndene forma formationformationtion by by cyclization cyclization of of a a ferrocenyl ferrocenyl-vinylferrocenyl--vinylvinyl carbocation. carbocation.carbocation.

InInIn aa variantvariantvariant of ofof this thisthis concept, concept,concept, the thethe diferrocenyl-alkynes diferrocenyldiferrocenyl--alkynesalkynes Fc–C FcFc––C≡CC≡CC–CH––CHCH2–Fc,22––Fc,Fc,12a 12a12a, and,, andand Fc–C FcFc––C≡CC–C(C≡C––=C(=O)C(=O)O)–Fc,–– ≡ ≡ Fc,12bFc, 12b,12b were,, werewere treated treatedtreated with withwith trifluoroacetic trifluoroacetictrifluoroacetic acidacid acid toto to formform form thethe theferrocenylferrocenyl ferrocenyl-stabilized--stabilizedstabilized vinylvinyl vinylcations,cations, cations, 13a13a,,bb [15]13a[15],.b. InIn[ 15 these these]. In systems, systems, these systems, cyclization cyclization cyclization occurred occurred by occurredby electrophilic electrophilic by electrophilic attack attack on on the theattack alkyl alkyl on-- oror the acyl acyl alkyl---linkedlinked or 5 ferrocenylacyl-linkedferrocenyl substituent substituentferrocenyl substituent to to form form (η (η to55--cyclopenta formcyclopenta (η -cyclopentadienyl)(3-ferrocenylpentalenyl)iron,dienyldienyl)(3)(3--ferrocenylpentalenyl)iron,ferrocenylpentalenyl)iron, 14a14a,, or or (η14a (η55--, cyclopentaorcyclopenta (η5-cyclopentadienyl)-(3-ferrocenyl-1-oxo-pentalenyl)iron,dienyldienyl))--(3(3--ferrocenylferrocenyl--11--oxooxo--pentalenyl)iron,pentalenyl)iron, 14b14b,, respectively,14brespectively,, respectively, asas depicteddepicted as depicted inin SchemeScheme in Scheme 4.4. 4.

Fe FFee Fe FFee XX ++ XX XX HH++ --HH++ FFee FFee HH FFee HH 1122aa,,bb 1133aa,,bb 1144aa,,bb XX == CCHH oorr CC==OO 22 SchemeScheme 4. 4. FerrocenopentaleneFerrocenopentalene formation formation by by cyclization cyclization of of a a ferrocenyl ferrocenyl-vinylferrocenyl--vinylvinyl carbocation. carbocation.

InInIn another another another remarkable remarkable remarkable example, example, example, protonation protonation protonation of the of of alkynylcycloheptatriene the the alkynylcycloheptatriene alkynylcycloheptatriene derivative, derivative, derivative,15, yielded 1515,, yielayiel ferrocenyl-stabilizeddedded a a ferrocenyl ferrocenyl--stabilizedstabilized vinyl cation, vinyl vinyl16 cation, cation,, that eventually1616,, that that eventually eventually yielded a yielded tricyclicyielded a aalcohol. tricyclic tricyclic The alcohol. alcohol. proposed The The proposedmechanismproposed mechanismmechanism (Scheme5 )(Scheme(Scheme involves 5)5) attack involvesinvolves by aattackattack double byby bond aa doubledouble of the bondbond trienyl ofof thethe unit trienyltrienyl at the unitunit vinylic atat thethe cation vinylicvinylic to cationgeneratecation to to the generate generate 6-ferrocenylbicyclo the the 6 6--ferrocenylbicyclferrocenylbicycl [3.2.2]nona-3,6,8-trien-2-yloo [[33.2.2.2.2]]nonanona--3,6,83,6,8 cation,--trtrienien17--2;2- subsequent-ylyl cation, cation, cyclopropyl1717;; subsequent subsequent ring cyclopropylclosurecyclopropyl yields ringring the closureclosure ferrocenyl-stabilized yieldsyields thethe ferrocenylferrocenyl cation--18stabilizedstabilized, and ultimately cationcation 1818 the,, andand alcohol ultimatelyultimately19 [15 the].the alcoholalcohol 1919 [15][15]..

Inorganics 2020, 8, 68 4 of 23 InorganicsInorganics 2020,, 8,, xx FORFOR PEERPEER REVIEWREVIEW 4 of 22

OH H Fc H Fc H Fc H + + + Fc Fc H Fc H2O

15 + 16 18 19 17 SchemeScheme 5. 5. CyclizationCyclization of of a a cycloheptatrienyl cycloheptatrienyl unit unit onto onto a a ferrocenyl ferrocenyl-vinyl--vinyl carbocatio carbocation.n.

AnotherAnother unexpected unexpected cyclization cyclization leading leading to to formation formation of ofa polycyclic a polycyclic system system was was reported reported by the by Schottenbergerthe Schottenberger group group who who prepared prepared the the ferrocenyl ferrocenyl allyl allyl alcohol alcohol 2020 thatthat underwent underwent an an allyl allyl rearrangementrearrangement thus thus forming forming a a vinylferrocene, vinylferrocene, 2121,,, therebythereby positioningpositioning the the hydroxy hydroxy substituent substituent near near thethe chain chain terminus. terminus. Treatment Treatment with with concentrated concentrated sulfuric sulfuric acid acid yielded yielded as as one one of of the the products products a a dimer dimer whose structure, shown in Scheme 66,, waswas establishedestablished byby X-ray X-ray crystallography crystallography [ [16]16]... TheThe authors authors advancedadvanced aa mechanismmechanism wherebywhereby elimination eliminationlimination of ofof water waterwater formed formedformed the thethe diene dienediene22 , 22 which,, whwhichich then thenthen participated participatedparticipated in a inin[4 +aa 2][4 Diels-Alder+ 2] Diels-Alder cycloaddition cycloaddition with the with ferrocenyl the ferrocenyl allyl cation allyl23 cationprior to23 eventual prior to indeneeventual formation. indene formation.One might One perhaps might more perhaps realistically more realistically envisage a stepwise envisage process a stepwise involving process electrophilic involving electrophilic attack by the attackallyl cation by the on allyl the cation diene toon form the diene the ferrocenyl-stabilized to form the ferrocenyl intermediate-stabilized24 intermediate, closure of the 24,, six-memberedclosureclosure ofof thethe sixring-membered to generate ring a di toff erentgenerate cationic a different site adjacent cationic to site the adjacent other ferrocenyl to the other moiety, ferrocenyl as in 25 moiety,, and finally as in 25ring,, andand closure finallyfinally onto ringring ferrocene, closureclosure ontoonto thus ferrocene,ferrocene, yielding the thusthus observed yieldingyielding final thethe productobservedobserved26 finalfinal. productproduct 26..

Me H H OH 22 Me Me + H+//H O -H 2 Fe Me Fe Fe Me + -H O Me Me OH 2 Me 20 21

Fe 23 Me Me Me

+ Me Fe Fe + Me Me Fe Me + Me Me -H+ +

Fe 26 Fe 25 24 Fe

SchemeScheme 6. DimerizationDimerization of of a a ferrocenyl ferrocenyl-allyl--allyl cation. cation.

AA second second fascinating fascinating observation observation from from the the same same laboratory laboratory resulted resulted from from the the protonation protonation of 1 of- ferrocenyl1-ferrocenyl-2,3,4,5-tetramethylcyclopent-2-en-1-ol,-2,3,4,5-tetramethylcyclopent-2-en-1-ol, 2727,, to to, to form form form 4 44-ferrocenyl-4-hydroxy-2,3,5,6-tetra--ferrocenyl-4-hydroxy-2,3,5,6-tetra- methyltetrahydropyran,methyltetrahydropyran, 2828[ 16 [16]]. The.. The The proposed proposed proposed mechanism mechanism mechanism involves involves involves initial initialinitial elimination elimination elimination of water of of together water water togetherwith a series with of a hydrideseries of shifts hydride to form shifts the to ferrocenyl-allylform the ferrocenyl cation-allyl29 that cation can 29 ring-open, that can ring in a- reversalopen, in ofa reversalthe normal of the Nazarov normal cyclization, Nazarov cyclization to generate,, to the generate divinylferrocenyl the divinylferrocenyl cation 30. Now, cation aqueous 30.. Now,Now, hydrolysis aqueousaqueous hydrolysisto form the to tetrahydropyran form the tetrahydropyran framework framework is followed is byfollowed addition by ofaddition a second of a molecule second molecule of water of to waterfurnish to the furnish final the product, final product,28, as illustrated 28,, asas illustratedillustrated in Scheme inin7 .SchemeScheme 7.7.

Inorganics 2020, 8, x FOR PEER REVIEW 5 of 22 Inorganics 2020, 8, 68 5 of 23 Inorganics 2020, 8, x FORMe PEER REVIEW Me Me 5 of 22 Me Me Me HO Me H+ M+e hydride Me Fc Fc + Me Me Me Fc Me -H O shifts HO H2+ + Me hydride Me H Fc + Fc Me Fc Me H Me Me shifts 27 -H2O H Me 29 rMetero Me H Me Nazarov 27 Me 29 retro Me Me Me Me Me Me Nazarov HO H2O + H2O Me H Me OMe Fc Me MOe Fc + Me Fc H HO H2O H2O H O Fc + O Fc + Me Me Me Me Me Me Fc 30 H 28 Me Me Me Me Me Me Scheme 7. Ferrocenyl28 -mediated retro-Nazarov ring-opening to form a hydroxytetramethyl30 - tetrahydropyran. SchemeScheme 7. Ferrocenyl-mediated 7. Ferrocenyl-mediated retro-Nazarov retro-Nazarov ring-opening ring-opening to form a tohydroxytetramethyl-tetrahydropyran. form a hydroxytetramethyl- 2.3. Ferrocenetetrahydropyran.-Mediated Cyclization to form Trisubstituted Aromatics, 1,3,5-C6H3(MLn)3 2.3. Ferrocene-Mediated Cyclization to form Trisubstituted Aromatics, 1,3,5-C6H3(MLn)3 Treatment of acetylferrocene with SiCl4/ethanol provides a convenient route to the specific 2.3. Ferrocene-Mediated Cyclization to form Trisubstituted Aromatics, 1,3,5-C6H3(MLn)3 formationTreatment of 1,3,5 of acetylferrocene-triferrocenylbenzene with SiCl[17]4./ ethanol This contrasts provides with a convenient the transition route metal to the-catalyzed specific formation of 1,3,5-triferrocenylbenzene [17]. This contrasts with the transition metal-catalyzed trimerizationsTreatment of of ethynylferrocene acetylferrocene with which SiCl yield4/ethanol a mixture provides of 1,2,4 a convenient and 1,3,5 route isomers to the[18,19] specific. The trimerizations of ethynylferrocene which yield a mixture of 1,2,4 and 1,3,5 isomers [18,19]. The proposed formationproposed mechanism of 1,3,5-triferrocenylbenzene shown in Scheme 8[17] involves. This initial contrasts reaction with of the the transitioncation [FcC(OH)CH metal-catalyzed3]+, 31, + trimerizationsmechanismwith the enol shown of form ethynylferrocene in of Scheme the ketone,8 involves which32; this initial yield process reaction a mixture continues of the of cation 1,2,4 in a and stepwise [FcC(OH)CH 1,3,5 mannerisomers3] , as[18,19]31 , the with . chain The the enol form of the ketone, 32; this process continues in a stepwise manner as the chain gradually grows,+ proposedgradually mechanismgrows, via intermediatesshown in Scheme 33 and 8 involves 34, prior initial to the reaction final dehydration of the cation leading [FcC(OH)CH to 35. This3] , is31 a, withviageneral intermediates the enolreaction form33 andand of the34 has ,ketone, prior also to the32 been; final this exploited processdehydration continues in leading the in case to a35 stepwise. of This (acet is a manneryl generalcyclopentadienyl as reaction the chain and)- graduallyhasmanganesetricarbonyl also been grows, exploited via intermediates which, in the case likewise, of 33 (acetylcyclopentadienyl)-manganesetricarbonyl and yields 34, the prior 1,3,5 to- trisubstitutedthe final dehydration aromatic leading [17]. Moreover, which, to 35. This likewise, mixed is a yields the 1,3,5-trisubstituted aromatic [17]. Moreover, mixed species are also accessible, as typified by generalspecies are reaction also accessible, and has as also typified been by theexploited Fe2Mn example, in the case36, shown of (acet in Figureylcyclopentadienyl 2; indeed, the)- manganesetricarbonylthebimetallic Fe2Mn Fe example,–Mn precursor,36 ,which, shown 37 likewise, in, corre Figuresponding yields2; indeed, the to 1,3,5 the33 bimetallicin-trisubstituted Scheme Fe–Mn 7 has aromatic also precursor, been [17] characterized. 37Moreover,, corresponding mixed by X- to 33 in Scheme7 has also been characterized by X-ray crystallography [ 20]. This approach has also speciesray crystallography are also accessible, [20]. This as typified approach by has the also Fe2Mn been example, used to 36 prepare, shown C in3h - Figuresymmetric 2; indeed, polycyclic the bimetallicbeensystems used [17] Fe to.– prepareMn precursor,C3h-symmetric 37, corre polycyclicsponding systemsto 33 in [Scheme17]. 7 has also been characterized by X- ray crystallography [20]. This approach has also been used to prepare C3h-symmetric polycyclic Me systems [17]CH. 31 3 H C Fc M+e OH Fc C+HOH 3 OH -H O+ O enolize 3 3 Fc 31 + H3C Fc HO Fc + OHHO H3C OH + O Fc Fc + OH Fc -H3O enolize H2C H2C Fc Fc + H3C 32 OFHc HO Fc 33 HO Fc H2C Fc H2C Fc Fc 32 OH Fc 33 Fc Fc Fc Fc Fc OH Fc + -H O Fc -H3O 2 CH2 CH OH Fc Fc OH 3 Fc OH Fc Fc -H O+ OH -H2O CH 3 + OFcH Fc 2 CH3 35 Fc Fc Fc Fc Fc 34 OH OFHc Fc + Fc Fc SchemeScheme35 8.8. ProposedProposed mechanismmechanism for for the the cyclization cyclization of of (CH (CH3C(3C(=O)C=O)C5H5H4F)ML4c)MLnn precursors,precursors, wherewhere ML MLnn= = 34 Fc Fe(CFe(C55H5)) or or Mn(CO) Mn(CO)33,, to to form form 1,3,5 1,3,5-trisubstituted-trisubstituted benzenes. benzenes. Scheme 8. Proposed mechanism for the cyclization of (CH3C(=O)C5H4)MLn precursors, where MLn =

Fe(C5H5) or Mn(CO)3, to form 1,3,5-trisubstituted benzenes.

Inorganics 2020, 8, 68 6 of 23 InorganicsInorganics 20 202020, ,8 8, ,x x FOR FOR PEER PEER REVIEW REVIEW 66 of of 22 22

FigureFigureFigure 2. 2.2. Molecular MolecularMolecular structures structuresstructures of ofof the thethe mixed mixedmixed iron iron-manganeseiron-manganese-manganese complexes complexes 36 36 and and 37 37.. .

InInIn some some ways, ways, the thethe ferrocenyl ferrocenyl group groupgroup behavior behaviorbehavior may maymay be bebe compared comparedcompared to toto that thatthat of ofof a apparentlyapparentlypparently related related 5 6 molecular fragments, such as (η -C5 H )Mn(CO) or (η 6-C H )Cr(CO) , which can also accommodate molecularmolecular fragments, fragments, such such as as (η (η5-C-C55H5H44)Mn(CO)4)Mn(CO)3 3or or (η (η6-C-C66H6H55)Cr(CO)5)Cr(CO)3,3 ,which which can can also also accommodate accommodate thethethe build build-upbuild-up-up ofof positive positive chargecharge on on an an adjacent adjacent atom atom [21] [21[21]] as,as, forfor example,example, in in thethe above-mentionedaboveabove-mentioned-mentioned preparation of 1,3,5-C H [(C H )Mn(CO) ] analogous to 1,3,5-triferrocenylbenzene [17]. However, preparationpreparation ofof 1,3,51,3,5-C-C66H6H3[(C3[(C55H5H44)Mn(CO)4)Mn(CO)3]33] 33 analoanalogousgous to to 1,3,51,3,5-triferrocenylbenzene-triferrocenylbenzene [17][17]. . However,However, thisthisthis is isis not not necessarily necessarily a a true true comparison comparison since since the the metal metal tricarbonyl tricarbonyl complexes complexescomplexes can cancan also alsoalso stabilize stabilizestabilize an anan α αα--carbanioncarbanion-carbanion through throughthrough delocalization delocalizationdelocalization of ofof the thethe negative negativenegative charge chargecharge onto ontoonto the thethe carbonyl carbonyl ligands ligands by by enhanced enhanced π backback-donationback-donation-donation of ofof electron electronelectron density densitydensity into intointo the the π* π** manifoldmanifold [[22]22[22]].. .This ThisThis is isis most most evident evident in in metal metal carbonyl carbonyl infrared stretching frequencies, ν , that decrease dramatically in the anions relative to their values in infraredinfrared stretching stretching frequencies, frequencies, ν COνCOCO, ,that that decrease decrease dramatically dramatically in in the the anions anions relative relative to to their their values values inthein the the corresponding corresponding corresponding cations. cations. cations. 3. Rearrangements of Vinylcyclopropenes 3.3. Rearrangements Rearrangements of of Vinylcyclopropenes Vinylcyclopropenes The thermal instability of vinylcyclopropenes is markedly enhanced when they also bear ferrocenyl TheThe thermal thermal instability instability of of vinylcyclopropenes vinylcyclopropenes is is markedly markedly enhanced enhanced when when they they also also bear bear substituents. Thus, decomposition of 3-cyclobutyl-3-ferrocenylcyclopropene, 38, brought about ferrocenylferrocenyl substituents. substituents. Thus, Thus, decomposition decomposition of of 3 3-cyclobutyl-cyclobutyl-3-3-fer-ferrocenylcyclopropene,rocenylcyclopropene, 38 38, ,brought brought rearrangement even at 0 C to give 3-cyclobutyliden-3-ferrocenylpropene, 39, and 3-cyclobutyl-1H- aboutabout rearrangement rearrangement even even◦ at at 0 0 °C °C to to give give 3 3-cyclobutyliden-cyclobutyliden-3-3-ferrocenylpropene,-ferrocenylpropene, 39 39, ,and and 3 3-cyclobutyl-cyclobutyl-- cyclopentaferrocene, 40 [23]. Mechanistically, one can invoke a ferrocenyl-stabilized diradical species 1H1H-cyclopentaferrocene,-cyclopentaferrocene, 4040 [23][23]. . Mechanistically, Mechanistically, one one can can invoke invoke a a ferrocenyl ferrocenyl-stabilized-stabilized diradical diradical or a vinyl carbene, as in Scheme9. The products can therefore arise either by hydrogen migration, or speciesspecies or or a a vinyl vinyl carbe carbene,ne, as as in in Scheme Scheme 9. 9. The The products products can can therefore therefore arise arise either either by by hydrogen hydrogen by attack on the ferrocenyl unit to form 39 or 40, respectively. migration,migration, or or by by attack attack on on the the ferrocenyl ferrocenyl unit unit to to form form 39 39 or or 40 40, ,respectively. respectively.

HH FFee FFee FFee

HH HH

HH HH H HH HH HH H 3388

H H H FFee HH H FFee HH HH HH HH 3399 4400

SchemeSchemeScheme 9. 9.9. Thermal ThermalThermal rearrangement rearrangementrearrangement of ofof 3 3-cyclobutyl-3-ferrocenylcyclopropene.3-cyclobutyl-cyclobutyl-3-3-ferrocenylcyclopropen-ferrocenylcyclopropene.e.

InInIn the the closelyclosely closely related related related system, system, system, 3-ferrocenyl-3-(2-ferrocenyl-1-methylvinylcyclopropene, 3 3-ferrocenyl-ferrocenyl-3-3-(2-(2-ferrocenyl-ferrocenyl-1-1-methylvinylcyclopropene,-methylvinylcyclopropene,41, which 41 41, ,which which bears bearstwobears ferrocenyl two two ferrocenyl ferrocenyl substituents, substituents, substituents, rearrangement rearrangement rearrangement occurs at 20occursoccurs◦C in at benzeneat 20 20 °C °C in solutionin benzene benzene to yieldsolution solution 1,4-diferrocenyl-5- to to yield yield 1,4 1,4-- diferrocenyldiferrocenyl-5-5-methylcyclopentadiene,-methylcyclopentadiene, 4242 (Scheme(Scheme 10). 10). Once Once again,again, the the intermediacy intermediacy of of a a vinyl vinyl carbenecarbene or or a a diradical diradical species species has has been been suggested suggested [24] [24]. .

Inorganics 2020, 8, 68 7 of 23

methylcyclopentadiene, 42 (Scheme 10). Once again, the intermediacy of a vinyl carbene or a diradical species has been suggested [24]. InorganicsInorganics 20 202020, ,,8 8, ,,x xx FOR FORFOR PEER PEERPEER REVIEW REVIEWREVIEW 77 of of 22 22

Fc FFcc Fc HH MMee HH H Me MMee HH Fc Me MMee Fc FFcc

H H H H FFcc H HH H H FFcc H HH 4411 42 42 SchemeScheme 10. 10. Thermal Thermal rearrangement rearrangement of of 3 3 3-ferrocenyl-3-(2-ferrocenyl-1-methylvinyl)cyclopropene.-ferrocenyl-ferrocenyl-3-3-(2-(2-ferrocenyl-ferrocenyl-1-1-methylvinyl-methylvinyl)cyclopropene.)cyclopropene.

4.4.4. Ferrocenyl Ferrocenyl Migration Migration onto onto an an Elect Electron-DeficientElectronron-Deficient-Deficient Carbon CarbonCarbon Cente CenterCenterr 4.1. Pinacol Rearrangements 4.1.4.1. Pinacol Pinacol Rearrangements Rearrangements Migratory aptitude is a widely invoked parameter to account for the selectivity and ease MigratoryMigratory aptitude aptitude is is a a widely widely invoked invoked parameter parameter to to account account for for the the selectivity selectivity and and ease ease of of of molecular rearrangements [25]. Typically, in cationic species, it is commonly assumed that a molecularmolecular rearrangements rearrangements [25] [25]. .Typically, Typically, in in cationic cationic species, species, it it is is commonly commonly assumed assumed that that a a phenyl phenyl phenyl migration is favored over that of its methyl counterpart because of charge delocalization in migrationmigration is is favored favored over over that that of of its its methyl methyl counterpart counterpart because because of of charge charge delocalization delocalization in in the the the phenonium ion transition state. However, such generalizations must be treated with caution. phenoniumphenonium ionion transitiontransition state.state. However,However, suchsuch generalizationsgeneralizations mustmust bebe treatedtreated withwith cauticaution.on. ForFor For example, upon protonation of the pinacol Ph2C(OH)-CMe2OH, it is a methyl that preferentially example,example, upon upon protonation protonation of of the the pinacol pinacol Ph Ph2C(OH)2C(OH)-CMe-CMe2OH2OH, , itit is is a a methyl methyl that that preferentially preferentially migrates (Scheme 11), not because the alkyl group has a better migratory aptitude than the aryl migratesmigrates (Scheme (Scheme 11), 11), not not because because the the alkyl alkyl group group has has a a better better migratory migratory aptitude aptitude than than the the aryl aryl substituent, but rather that the more favored carbocation, 43, is doubly benzylic [26]. substituent,substituent, but but rather rather that that the the more more favored favored carbocation, carbocation, 43 43, ,is is doubly doubly benzylic benzylic [26] [26]. .

PPhh PPhh Ph OH PPhh Ph OH ++ Ph ++ + + PPhh HH+ PPhh --HH+ Ph Me Me MMee OOHH Me OOHH Me OO OH - H O - H22O MMee MMee MMee 4433 43 SchemeScheme 11. 11.11. Pinacol Pinacol rearrangement rearrangement showing showing methyl methyl rather rather than than phenyl phenyl migration. migration.migration. To make a fair comparison, for example between phenyl and ferrocenyl, one must eliminate ToTo make make a a fair fair comparison, comparison, for for example example between between phenyl phenyl and and ferrocenyl, ferrocenyl, one one must must eliminate eliminate such such such extraneous factors. This was first discussed by Weliky and Gould [27] in 1956 who prepared extraneousextraneous factors.factors. TThishis waswas firstfirst discusseddiscussed byby WelikyWeliky andand GouldGould [27][27] inin 19561956 whowho preparedprepared 1,21,2-- 1,2-diferrocenyl-1,2-diphenyl-ethanediol, 44, by treatment of benzoylferrocene with cobalt dichloride diferrocenyldiferrocenyl-1,2-1,2-diphenyl-diphenyl-ethanediol,-ethanediol, 44 44, ,by by treatment treatment of of benzoylferrocene benzoylferrocene with with cobalt cobalt dichloride dichloride in in in the presence of a Grignard reagent. They noted that this pinacol “rearranged with remarkable thethe presence presence of of a a Grignard Grignard reagent. reagent. They They noted noted that that this this pinacol pinacol “ “rearrangedrearranged with with remarkable remarkable ease ease ease (merely upon passing gaseous HCl over its solution in benzene) to the pinacolone 45.” Clearly, (merely(merely upon upon passing passing gaseous gaseous HCl HCl over over its its solution solution in in benzene) benzene) to to the the pinacolone pinacolone 4545.”.” Clearly,Clearly, ferrocenyl was favored over phenyl migration, as in Scheme 12. Later work by several groups [28–30] ferrocenylferrocenyl was was favored favored over over phenyl phenyl migration, migration, as as in in Scheme Scheme 12. 12. Later Later work work by by several several groups groups [28 [28–– 30]revealed,30] revealed, revealed, not not not surprisingly, surprisingly, surprisingly, that that that ferrocenyl ferrocenyl ferrocenyl migration migration migration was was was also also also favored favored favored over over over anan an alkylalkyl alkyl shift shift (R (R = == Me, Me, 30] nrevealed,n not surprisingly, that ferrocenyl migration was also favored over an alkyl shift (R = Me, Et, n Pr, n Bu). Subsequently, however, it was found that phenyl migration in cation 46 is indeed Et,Et, Pr,nPr, Bu).nBu). Subsequently, Subsequently, however, however, it it was was found found that that phenyl phenyl migration migration in in cation cation 4646 isis indeed indeed observable, but that the ferrocenyl shift was preferred by a factor of ~8. Interestingly, it was noted that observable,observable, but but that that the the ferrocenyl ferrocenyl shift shift was was preferred preferred by by a a factor factor of of ~8. ~8. Interestingly, Interestingly, it it was was noted noted the rearrangement behavior of the threo and erythro isomers of 44 was identical [31]. thatthat the the rearrangement rearrangement behavior behavior of of the the threo threo and and erythro erythro isomers isomers of of 44 44 was was identical identical [31] [31]. .

PPhh Ph Ph OH Ph PPhh Fc OH ++ Fc ++ + Fc + FFcc HH+ Fc --HH+ -H Fc Fc Fc OO Fc OOHH - H O FFcc OH OH - H22O OH PPhh PPhh PPhh 4444 4466 4455 46 45 SchemeScheme 12. 12. Pinacol Pinacol rearrangement rearrangement showing showing favored favored migration migration of of ferrocenyl ferrocenyl over overover phenyl. phenyl.phenyl.

MuchMuch more more recently, recently, a a comprehensive comprehensive study study of of the the modified modified Clemmensen Clemmensen reduction reduction of of formylferrocene,formylferrocene, acetylferrocene acetylferrocene, ,and and benzoylferrocene benzoylferrocene was was reported reported by by Bildstein Bildstein [32] [32]. .In In this this case, case, thethe normal normal reagents, reagents, Zn/HCl, Zn/HCl, were were replaced replaced by by Zn/Me Zn/Me3SiCl3SiCl in in the the expectati expectationon that that deoxygenation deoxygenation to to obtainobtain the the corresponding corresponding alkenes, alkenes, R(Fc)C=C(Fc)R, R(Fc)C=C(Fc)R, would would be be enhanced enhanced by by formation formation of of Me Me3Si3Si––OO––

Inorganics 2020, 8, 68 8 of 23

Much more recently, a comprehensive study of the modified Clemmensen reduction of formylferrocene, acetylferrocene, and benzoylferrocene was reported by Bildstein [32]. In this case, Inorganics 2020,, 8,, xx FORFOR PEERPEER REVIEWREVIEW 8 of 22 the normal reagents, Zn/HCl, were replaced by Zn/Me3SiCl in the expectation that deoxygenation to obtain the corresponding alkenes, R(Fc)C=C(Fc)R, would be enhanced by formation of Me Si–O–SiMe SiMe3 with its energetically favorable silicon-oxygen linkages. Experimentally, however, 3as shown in3 Schemewith its energetically 13, the isolated favorable silicon-oxygenproducts were linkages trans.- Experimentally,however,diferrocenylethene, 47, as 2,3 shown-diferrocenyl in Scheme-2,3 13-, bis(trimethylsiloxy)butane,the isolated products were trans 48, and-diferrocenylethene, 2,2-diferrocenyl-471,2, 2,3-diferrocenyl-2,3-bis(trimethylsiloxy)butane,-diphenyl-ethan-1-one, 49, respectively. These three48, and products 2,2-diferrocenyl-1,2-diphenyl-ethan-1-one, were each unambiguously characterized49, respectively. by X-ray crystallography. These three products It is reasonable were each to assuunambiguouslyme that the pinacolone, characterized 49 by, must X-ray have crystallography. been derived It from is reasonable the diphenyl to assume analogue that of the the pinacolone, disiloxy- pinacol49, must 48 have. Related been work derived in fromthis area, the diphenylincluding analogue synthetic of routes the disiloxy-pinacol to ferrocenyl cumulenes,48. Related has work been in fullythis area, reviewed including elsewhere synthetic [33] routes. to ferrocenyl cumulenes, has been fully reviewed elsewhere [33].

Fc Fc H Zn/Me3SiCl Fc O H 47 H H Fc

Fc Fc Fc Zn/Me3SiCl TMSO O OTMS Me Me Me Me 48 Ph Fc Fc Zn/Me3SiCl O Fc O Ph O 49

Ph SchemeScheme 13. 13.Experimentally Experimentally observed observed products products derived derivedfrom Clemmensen from Clemmensen reduction of formylferrocene,reduction of formylferrocene,acetylferrocene, and acetylferrocene benzoylferrocene., and benzoylferrocene.

TheseThese results results may may be compared with those found in in the course of the closely analogous McMurryMcMurry reaction of of ( (ηη55-acetylcyclopentadienyl)(-acetylcyclopentadienyl)(ηη4--tetraphenylcyclobutadiene)cobalt,tetraphenylcyclobutadiene)cobalt, 5050,, with with benzobenzophenonephenone [34] [34.]. The The products products observed observed in addition in addition to the desired to the desiredhetero-coupled hetero-coupled alkene, 51 alkene,, were trans51, were-2,3-bis[(ηtrans-2,3-bis[(5-cyclopentaη5-cyclopentadienyl)(dienyl)(η4-tetraphenylcyclobutadienecobalt]η4-tetraphenylcyclobutadienecobalt]-2-butene,-2-butene, 52, and 3,523,- andbis- [(η3,3-bis-[(5-cyclopentadienylη5-cyclopentadienyl)()(η4-tetraphenylcyclobutadiene)cobalt]butanη4-tetraphenylcyclobutadiene)cobalt]butan-2-one,-2-one, 53, which53, which parallel parallel the structuresthe structures of Bildstein’s of Bildstein’s iron iron complexes, complexes, 47 and47 and 49. Once49. Once again, again, the homo the homo-coupled-coupled alkene alkene adopts adopts the transthe trans structure,structure, and and it is it the is the cobalt cobalt sandwich sandwich moiety moiety that that has has migrated migrated to to form form the the pinacolone, pinacolone, as as shownshown in in Scheme Scheme 14.14.

51 Ph [Co] Ph O Me [Co] Ph Me Ph TiCl4 / Zn [Co] [Co] = + + + O Co O Ph THF [Co] Me Ph [Co] THF O Me Ph Ph O Me [Co] 53 Ph Ph Me 52 [Co] 50 52 50 SchemeScheme 14. ExperimentallyExperimentally observed observed products products derived derived from from the the McMurry McMurry reaction reaction of 55 4 4 [(η[(η5--MeC(MeC(=O)C=O)C5H5H4)Co(η4)Co(4η-C-C4Ph4Ph4)]4 with)] with benz benzophenone.ophenone.

This reaction was important for the development of a synthetic route to cobaltifens, 54, (Scheme 15) [35], the cobalt analogues of ferrocifens, 55, that are now under intensive investigation for their activity against breast cancers and other related diseases [36] (see Section 7).

Inorganics 2020, 8, 68 9 of 23

This reaction was important for the development of a synthetic route to cobaltifens, 54, (Scheme 15)[35], the cobalt analogues of ferrocifens, 55, that are now under intensive investigation for theirInorganics activity 2020, against8, x FOR PEER breast REVIEW cancers and other related diseases [36] (see Section7). 9 of 22 Inorganics 2020, 8, x FOR PEER REVIEW 9 of 22

OH OH OH OH Et EEtt EEtt Et Et Et (i) (i) O O CCoo CCoo FFee Ph Co (ii) (iii) Co Fe Ph Ph (ii) (iii) PPhh Ph Ph Ph Ph PPhh Ph Ph Ph Ph Ph Ph Ph OO--((CCHH2))nNNMMee2 OO--((CCHH2))nNNMMee2 5544 O-(CH2)nNMe2 5555 O-(CH2)nNMe2 54 55 Scheme 15. Synthetic route to cobaltifens: reagents (i) (p-HOC6H4)2C=O, Zn, TiCl4, THF; (ii) NaH, Scheme 15.15. Synthetic route route toto cobaltifens: cobaltifens: reagentsreagents (i) (i) ((pp-HOC-HOC66HH44)2C=O,C=O, Zn, Zn, TiCl TiCl44, ,THF; THF; (ii) (ii) NaH, NaH, DMF, (iii) Cl(CH2)nNMe2, NEt3, THF. DMF, (iii) Cl(CHCl(CH22)nNMeNMe22, ,NEt NEt3,3 ,THF. THF.

FollowingFollowing thethe mechanisticmechanistic proposals proposals ofof Bogdanović Bogdanovi´c[Bogdanović [37][37]37] andand ofof GeiseGeise [38] [[38]38],,, itit waswas suggestedsuggested thatthat oneone couldcould visualize visualize formation formation of of the thetrans trans-alkene-alkene52 52from from the theC2-symmetric C2-symmetric intermediate intermediate56 (Scheme 56 (Scheme 16). one could visualize formation of the trans-alkene 52 from the C2-symmetric intermediate 56 (Scheme cis 16).In16). contrast, In In contrast, contrast, when when when the the the bulky bulky bulky metallocenyl metallocenyl metallocenyl groups groups groups are are are positioned positioned positioned in in in a a a cis cisfashion, fashion, fashion, alkenealkene alkene formation formationformation maymay bebe stericallysterically hinderedhindered andand insteadinstead aa pinacolpinacol-to-pinacolonepinacol--toto--pinacolonepinacolone rearrangementrearrangement viavia aa metalmetal-stabilizedmetal--stabilizedstabilized cationiccationic structure,structure, 57 57,,, isisis thethethe preferredpreferredpreferred option optionoption (Scheme (Scheme(Scheme 17 17).17).). ClTiO OTiCl ClTiO OTiCl --22 TTiiOOCCll Me [[CCoo]] -2 TiOCl Me [[CCoo]] Me [Co] Me CC CC [Co] [Co] C C [Co] Me [Co] MMee [Co] Me Me 5566 5522 [Co] = (C H )Co(C Ph ) [Co] = (C55H44)Co(C44Ph44) 5 4 4 4 4 4 5 4 SchemeScheme 16.16. McMurryMcMurry couplingcoupling ofof (C(C4PhPh4)Co[C)Co[C5HH4C(=O)Me]C(=O)Me] toto formform thethe transtrans--alkenealkene,, 5252.. SchemeScheme 16.16. McMurryMcMurry couplingcoupling ofof (C(C44PhPh44)Co[C5HH44C(=O)Me]C(=O)Me] to to form form the the transtrans-alkene-alkene,, 5252. . O-- - O OO- Cl CCll CCll TTiiCl Ti CCll OTi Cl [Co] Ti TTiiCl O Cl [Co] OO OO OO OO CCll Me Me O + Me Me MMee Me Me MMee + MMee Ph --TTiiOOCCll2 Me Me Me Me Me PPhh Ph -TiOCl2 [[CCoo]] ++ Ph MMee [Co] [Co] [Co] [Co] C+o [[CCoo]] Me [[CCoo]] [Co] [Co] [Co] Co Ph PPhh Ph Ph 53 [Co] = (C H )Co(C Ph ) 57 53 [Co] = (C55H44)Co(C44Ph44) 57 5 4 4 4 SchemeScheme 17. 17.Pinacolone Pinacolone formation formation in in a a McMurry McMurry reaction reaction of of (C (CPh4Ph)Co[C4)Co[C5HH4C(C(=O)Me].=O)Me]. Scheme 17. Pinacolone formation in a McMurry reaction of (C44Ph44)Co[C5H4C(=O)Me].

The corresponding bridging structure, 58, that facilitates a ferrocenyl migration would serve the TheThe corresponding corresponding bridging bridging structure, structure, 58 58,, that that facilitates facilitates a a ferrocenyl ferrocenyl migration migration would would serve serve the the same purpose (but markedly more efficiently) as the phenonium ion, 59, that allows delocalization of samesame purposepurpose (but(but markedlymarkedly moremore efficefficiently)iently) asas thethe phenoniumphenonium ion,ion, 5959,, thatthat allowsallows delocalizationdelocalization positive charge in the transition state for phenyl migrations (Figure3). ofof positivepositive chargecharge inin thethe transitiontransition statestate forfor phenylphenyl migrationsmigrations (Figure(Figure 3).3).

R RR R R RR R RR R RR R RR RR R

FFee 5588 5599 58 59 Figure 3. Transition states for ferrocenyl and phenyl rearrangements whereby positive charge is Figure 3. Transition states for ferrocenyl and phenyl rearrangements whereby positive charge is delocalized onto the migrating group. delocalized onto the migrating group.

AA particularly particularly fascinating fascinating pinacol pinacol--toto--pinacolonepinacolone rearrangement rearrangement was was reported reported by by Härter Härter and and colleaguescolleagues who who studied studied the the McMurry McMurry reactionreaction of of [3][3]ferrocenophanoneferrocenophanone underunder differentdifferent conditions conditions [39]. When the standard reagent system (TiCl4/Zn) was augmented with pyridine, the homo-coupled [39]. When the standard reagent system (TiCl4/Zn) was augmented with pyridine, the homo-coupled

Inorganics 2020, 8, x FOR PEER REVIEW 9 of 22

OH OH Et Et Et (i) O Co Co Fe Ph (ii) (iii) Ph Ph Ph

Ph Ph Ph Ph

O-(CH2)nNMe2 O-(CH2)nNMe2 54 55

Scheme 15. Synthetic route to cobaltifens: reagents (i) (p-HOC6H4)2C=O, Zn, TiCl4, THF; (ii) NaH,

DMF, (iii) Cl(CH2)nNMe2, NEt3, THF.

Following the mechanistic proposals of Bogdanović [37] and of Geise [38], it was suggested that one could visualize formation of the trans-alkene 52 from the C2-symmetric intermediate 56 (Scheme 16). In contrast, when the bulky metallocenyl groups are positioned in a cis fashion, alkene formation may be sterically hindered and instead a pinacol-to-pinacolone rearrangement via a metal-stabilized cationic structure, 57, is the preferred option (Scheme 17).

ClTiO OTiCl -2 TiOCl [Co] [Co] Me Me C C [Co] [Co] Me Me 56 52 [Co] = (C H )Co(C Ph ) 5 4 4 4

Scheme 16. McMurry coupling of (C4Ph4)Co[C5H4C(=O)Me] to form the trans-alkene, 52.

O - O- Cl Cl Ti Cl Ti Ti Cl O Cl [Co] O O O O Cl Me Me Me + Me -TiOCl Me Me Me Ph Ph 2 [Co] + [Co] Me [Co] [Co] [Co] [Co] Co Ph Ph 53 [Co] = (C H )Co(C Ph ) 57 5 4 4 4

Scheme 17. Pinacolone formation in a McMurry reaction of (C4Ph4)Co[C5H4C(=O)Me].

The corresponding bridging structure, 58, that facilitates a ferrocenyl migration would serve the sameInorganics purpose2020, 8, 68(but markedly more efficiently) as the phenonium ion, 59, that allows delocalization10 of 23 of positive charge in the transition state for phenyl migrations (Figure 3).

R R R R R R R R

Fe

58 59 Figure 3. TransitionTransition states states for for ferrocenyl ferrocenyl and and phenyl rearrangements whereby positivpositivee charge is delocalized onto the migrating group.

A particularly fascinating pinacolpinacol-to-pinacolone-to-pinacolone rearrangement rearrangement was was reported reported by by Härter and colleagues who studied the McMurry reaction of [3]ferrocenophanone under different conditions [39]. colleaguesInorganics 2020 who, 8, x FOR studied PEER theREVIEW McMurry reaction of [3]ferrocenophanone under different conditions10 of 22 When the standard reagent system (TiCl /Zn) was augmented with pyridine, the homo-coupled [39]. When the standard reagent system (TiCl4 4/Zn) was augmented with pyridine, the homo-coupled product bis-[3]ferrocenophane-1-ylidene, 60, (as an E/Z mixture) was obtained in 70% yield (Scheme 18). product bis-[3]ferrocenophane-1-ylidene, 60, (as an E/Z mixture) was obtained in 70% yield (Scheme In18). contrast, In contrast, in the in absence the absence of pyridine, of pyridine, the major the product major wasproduct the spiro-linked was the spir pinacoloneo-linked pinacolone61, which was 61, unequivocallywhich was unequivocally characterized characterized by X-ray crystallography. by X-ray crystallography.

Fe O Fe Zn, TiCl4 60(Z) Fe + pyridine

Fe

Fe Zn, TiCl 4 60(E)

Fe Fe + Fe OH Fe O 61 Scheme 18. McMurry coupling and pinacol rearrangement of [3]ferrocenophanone.[3]ferrocenophanone.

4.2. Wolff Wolff Rearrangements Thermal or photochemical dissociationdissociation of α -diazoketones-diazoketones liberates nitrogen to form the corresponding ketene. Whether Whether the the reaction reaction involves formation formation of of free carbenes, or proceeds via a concerted processprocess isis stillstill the the subject subject of of discussion. discussion. Nevertheless, Nevertheless, the the ketenes ketenes produced produced by by migration migration of theof the alkyl alkyl group group onto onto the the electron-deficient electron-deficient carbon carbon are are versatile versatile species species thatthat reactreact with nucleophiles, such as water, alcoholsalcohols oror amines,amines, to formform carboxylic acids, esters,esters, or amides, but are also routinely used as partners in [2[2 ++ 2]2] cycloadditions [[4040].]. Diphenylketene is is a a stable solid but the existence of ferrocenylketene, 62,, hashas onlyonly been verifiedverified spectroscopicallyspectroscopically byby laserlaser flashflash photolysis,photolysis, andand waswas then trapped by reaction with n-butylamine-butylamine [[41]41].. Similarly, thethe bis-ketenebis-ketene 63 is detectable in the photolysis of 1,2-diferrocenyl-1-cyclobuten-3,4-dione1,2-diferrocenyl-1-cyclobuten-3,4-dione (Scheme(Scheme 1919).).

O + H O N N -N2 C C O - RNH Fe 2 NHR H Fe Fe 62

O O O O C C

Fe Fe Fe Fe 63 Scheme 19. Generation of ferrocenylketene, 62, and bis-ferrocenylketene, 63.

4.3. Rearrangements of Alkynyl-4-hydroxy-2-cyclobutenones In the continuing search for novel anti-cancer agents, the 2-alkylidene-4-cyclopentene-1,3-dione framework [42] has attracted considerable recent attention. The remarkable bioactivity of ferrocenyl- containing molecules, in particular the ferrocifens [36], prompted the preparation of a series of 2- ferrocenylidene-4,5-dialkyl-4-cyclopenten-1,3-diones, 64. As shown in Scheme 20, these molecules

Inorganics 2020, 8, x FOR PEER REVIEW 10 of 22 product bis-[3]ferrocenophane-1-ylidene, 60, (as an E/Z mixture) was obtained in 70% yield (Scheme 18). In contrast, in the absence of pyridine, the major product was the spiro-linked pinacolone 61, which was unequivocally characterized by X-ray crystallography.

Fe O Fe Zn, TiCl4 60(Z) Fe + pyridine

Fe

Fe Zn, TiCl 4 60(E)

Fe Fe + Fe OH Fe O 61 Scheme 18. McMurry coupling and pinacol rearrangement of [3]ferrocenophanone.

4.2. Wolff Rearrangements Thermal or photochemical dissociation of α-diazoketones liberates nitrogen to form the corresponding ketene. Whether the reaction involves formation of free carbenes, or proceeds via a concerted process is still the subject of discussion. Nevertheless, the ketenes produced by migration of the alkyl group onto the electron-deficient carbon are versatile species that react with nucleophiles, such as water, alcohols or amines, to form carboxylic acids, esters, or amides, but are also routinely used as partners in [2 + 2] cycloadditions [40]. Diphenylketene is a stable solid but the existence of ferrocenylketene, 62, has only been verified spectroscopically by laser flash photolysis, and was then Inorganicstrapped2020 by ,reaction8, 68 with n-butylamine [41]. Similarly, the bis-ketene 63 is detectable in the photolysis11 of 23 of 1,2-diferrocenyl-1-cyclobuten-3,4-dione (Scheme 19).

O + H O N N -N2 C C O - RNH Fe 2 NHR H Fe Fe 62

O O O O C C

Fe Fe Fe Fe 63 SchemeScheme 19.19. GenerationGeneration ofof ferrocenylketene,ferrocenylketene,62 62,, andand bis-ferrocenylketene,bis-ferrocenylketene,63 63.. Inorganics 2020, 8, x FOR PEER REVIEW 11 of 22 4.3. Rearrangements of Alkynyl-4-hydroxy-2-cyclobutenones are4.3. formed,Rearrangements along with of Alkynyl their -isomeric4-hydroxy benzoquinones,-2-cyclobutenone s65 , when 4-ferrocenyl-ethynyl-4-hydroxy-2- cyclobutenones,InIn thethe continuingcontinuing 66, undergo searchsearch thermal forfor novelnovel rearrangement anti-canceranti-cancer agents,agents, when the theheated 2-alkylidene-4-cyclopentene-1,3-dione2-alkylidene at reflux- in4- cyclopentenedioxane [43].- 1,3-dione frameworkframeworkAlthough [[42]42 ]this hashas reaction attractedattracted does considerableconsiderable not start from recentrecent a attention.diazoketone,attention. TheThe the remarkableremarkable intermediacy bioactivitybioactivity of a ketene, of ferrocenyl-ferrocenyl and the- containingrolecontaining of the ferrocenyl molecules,molecules, unit in inparticular stabilizing the the adjacent ferrocifens ferrocifens cations [36] [36 or,], prompted radicals, prompted reveal the the preparation preparationsome parall ofels of a to aseries the series Wolff of of2- 2-ferrocenylidene-4,5-dialkyl-4-cyclopenten-1,3-diones,rearrangement.ferrocenylidene Upon-4,5-dialkyl heating,-4-cyclopenten 66 undergoes-1,3 electrocyclic-diones, 6464 .ring .As As shownopening shown in into Scheme Schemeform the 2020, conjugated, thesethese moleculesmolecules ketene are67 that formed, can ring along-close with in theirtwo different isomeric ways. benzoquinones, In each case,65 ,the when diradical 4-ferrocenyl-ethynyl-4-hydroxy-2- so-formed then proceeds by cyclobutenones,hydrogen migration66, undergo to yield thermalthe observe rearrangementd products. when heated at reflux in dioxane [43].

O O R O Fc R C R Fc Fc R R R OH OH 66 OH 67

O O R O H R R Fc Fc Fc R R R H 64 O OH O 65 SchemeScheme 20. 20.Rearrangement Rearrangement of 4-ferrocenylethynyl-4-hydroxy-2-cyclobutenones of 4-ferrocenylethynyl-4-hydroxy-2-cyclobutenones into 2-ferrocenylidene- into 2- 4-cyclopenten-1,3-dionesferrocenylidene-4-cyclopenten and 5-ferrocenyl-1,4-benzoquinones.-1,3-diones and 5-ferrocenyl-1,4-benzoquinones.

AlthoughInterestingly, this when reaction R ≠ does R’, the not two start geometric from a diazoketone, isomers 64a theand intermediacy 64b interconvert of a ketene,when heated and the at role125 °C, of the and ferrocenyl it has been unit suggested in stabilizing that a adjacentzwitterionic cations contribution, or radicals, 68 reveal, to the some structure parallels would tothe facilitate Wolff rearrangement.rotation about the Upon C=CHFc heating, linkage66 undergoes (Scheme electrocyclic21). ring opening to form the conjugated ketene 67 that can ring-close in two different ways. In each case, the diradical so-formed then proceeds by hydrogen migration to yield the observed products. O O O _ Interestingly,R when R , R’, the two geometric isomers 64a and 64bR interconvert when heated at H R Fc Fc 125 ◦C, and it has been suggested that a zwitterionic contribution,? 68, to the structure+ would facilitate rotation about the C=CHFc linkage (Scheme 21). Fc H H R' R' R' O 64a O O 64b 68 Scheme 21. Proposed mechanism for the interconversion of 42a and 42b via a zwitterionic structure.

In a somewhat comparable situation, the potential push-pull ferrocenylidene-fluorenyl allene, 69, that was synthesized by Meyer-Schuster rearrangement of the precursor alkynol with thionyl chloride (Scheme 22), was investigated to test the possibility that the terminal groups might stabilize the separate charges thus generating carbene character at the allene central carbon. Although the 13C NMR spectrum of 69 revealed a peak at 198 ppm, in the normal range for the central carbon in an allene, the molecule was stable only below −20 °C and readily dimerized [44].

O OH O S Cl SOCl2 -SO2 Cl ? _ + Cl C -HCl C C C C C Fc C C Fc Fc Fc 69 Scheme 22. Meyer-Schuster rearrangement of an alkynol to form the potential push-pull allene, 69.

Inorganics 2020, 8, x FOR PEER REVIEW 11 of 22 are formed, along with their isomeric benzoquinones, 65, when 4-ferrocenyl-ethynyl-4-hydroxy-2- cyclobutenones, 66, undergo thermal rearrangement when heated at reflux in dioxane [43]. Although this reaction does not start from a diazoketone, the intermediacy of a ketene, and the role of the ferrocenyl unit in stabilizing adjacent cations or radicals, reveal some parallels to the Wolff rearrangement. Upon heating, 66 undergoes electrocyclic ring opening to form the conjugated ketene 67 that can ring-close in two different ways. In each case, the diradical so-formed then proceeds by hydrogen migration to yield the observed products.

O O R O O R O R Fc R C R Fc Fc R Fc R R R R OH OH 66 OH 67

O O O O R R O H R R Fc Fc R Fc Fc R R R H 64 O OH OH O 65 O 65 Scheme 20. Rearrangement of 4-ferrocenylethynyl-4-hydroxy-2-cyclobutenones into 2- ferrocenylidene-4-cyclopenten-1,3-diones and 5-ferrocenyl-1,4-benzoquinones.

Interestingly, when R ≠ R’, the two geometric isomers 64a and 64b interconvert when heated at 125 °C, and it has been suggested that a zwitterionic contribution, 68, to the structure would facilitate Inorganics125 °C, and2020 ,it8 ,has 68 been suggested that a zwitterionic contribution, 68, to the structure would facilitate12 of 23 rotation about the C=CHFc linkage (Scheme 21).

O _ O O O _ R R H R R Fc H R Fc ? Fc ? + Fc R' Fc R' H H R' R' R' O O 64a O 64b O 68 64b 68 SchemeScheme 21.21. Proposed mechanism for the interconversioninterconversion ofof 42a42a andand 42b42b viavia aa zwitterioniczwitterionic structure.structure.

In a somewhat comparable situation, the potential push-pull ferrocenylidene-fluorenyl allene, In a somewhat comparable situation, the potential push-pull ferrocenylidene-fluorenyl allene, 69, that was synthesized by Meyer-Schuster rearrangement of the precursor alkynol with thionyl 69, that was synthesized by Meyer-Schuster rearrangement of the precursor alkynol with thionyl chloride (Scheme 22), was investigated to test the possibility that the terminal groups might stabilize chloride (Scheme 22), was investigated to test the possibility that the terminal groups might stabilize 13 the separate charges thus generating carbene character at the allene central carbon. Although the 13C the separate charges thus generating carbene character at the allene central carbon. Although the 13C NMR spectrum of 69 revealed a peak at 198 ppm, in the normal range for the central carbon in an NMR spectrum of 69 revealed a peak at 198 ppm, in the normal range for the central carbon in an allene,allene, thethe moleculemolecule waswas stablestable onlyonly belowbelow −20 ◦°CC and readily dimerized [[44]44].. allene, the molecule was stable only below −−20 °C and readily dimerized [44].

O OH O S Cl SOCl2 O S ? Cl SOCl2 -SO2 Cl ? _ + Cl 2 Cl C -HCl Cl C C C C -HCl C Fc C C Fc Fc C Fc C Fc Fc 69 Inorganics 2020, 8, x FOR PEER REVIEW 69 12 of 22 SchemeScheme 22.22. Meyer-SchusterMeyer-Schuster rearrangement ofof anan alkynolalkynol toto formform thethe potentialpotential push-pullpush-pull allene,allene, 6969.. 5. Ferrocenyl Migration onto an Electron-Deficient Nitrogen Center 5. Ferrocenyl Migration onto an Electron-Deficient Nitrogen Center 5.1. Beckmann Rearrangements 5.1. Beckmann Rearrangements Oximes are readily preparable by reaction of the precursor aldehyde or ketone with Oximes are readily preparable by reaction of the precursor aldehyde or ketone with hydroxylamine hydroxylamine hydrochloride [45]. When treated with reagents (e.g., H2SO4, PCl5, or SOCl2) that hydrochlorideconvert the hydroxyl [45]. When into treateda leaving with group, reagents it brings (e.g., about H2SO 4migration, PCl5, or SOClof the2) anti that substituent convert the to hydroxyl form a intonitrilium a leaving ion, 70 group,; typically, it brings Beckmann about migration rearrangement of the ofanti thesubstituent ferrocenyl to oxime form 71 a nitriliumand subsequent ion, 70; typically,hydrolysis Beckmann yielded the rearrangement secondary amide of the ferrocenyl72 (Scheme oxime 23) [46]71 and. This subsequent specific geometric hydrolysis requirement yielded the secondarycontrasts with amide the72 situation(Scheme in 23 the)[ 46pinacol]. This rearrangement specific geometric whereby requirement the identity contrasts of the with migrating the situation group inis controlled the pinacol primarily rearrangement by its whereby migratory the aptitude identity ofrather the migratingthan its geometric group is controlledalignment. primarily Interestingly, by its migratoryseveral carbamate aptitude rather derivatives than its of geometric ferrocenyl alignment. ketoximes Interestingly, have demonstrated several carbamate acetylcholin derivatives-esterase of ferrocenylactivity [47] ketoximes. have demonstrated acetylcholin-esterase activity [47].

Fc + H + H2O N Fc-N=C-R Fc-NH-C(=O)R R -H O OH 2 71 70 72

Scheme 23. Beckmann rearrangement of a ferrocenyl oxime.

While the Beckmann reaction was extensively explored in pioneering investigations by Schlögl involving a range of alkyl alkyl-- or aryl aryl-substituted-substituted ferrocenyl oximes, probably the most explicit examples are those derived from ferrocenocyclohexanones, asas inin SchemeScheme 2424.. In these cases, the structures of the resulting ferrocenocaprolactams,ferrocenocaprolactams,73 73and and74 74, are, are clearly clearly controlled controlled by theby thesyn orsynanti or orientationanti orientation of their of precursortheir precursor oximes oximes [46]. [46].

OH HO O N O N H N + NH H H+ Fe Fe Fe Fe 73 74 Scheme 24. Beckmann rearrangement of anti and syn ferrocenocyclohexanone oximes.

5.2. Curtius Rearrangements Thermolysis of acyl azides proceeds with loss of nitrogen to form isocyanates. Although they can be isolated, the reaction is often carried out in the presence of a nucleophilic solvent such as an alcohol or amine to form esters or ureas. In contrast to the Wolff rearrangement that can proceed via a carbene intermediate, the Curtius rearrangement is almost certainly a concerted process that does not involve a discrete nitrene [25]. Rearrangement of ferrocenoyl azide, 75, by thermolysis in refluxing dry toluene furnished ferrocenyl isocyanate, 76. As shown in Scheme 25, reaction with ethanol or water produces ethyl ferrocenylcarbamate, 77, or ferrocenylcarbamic acid, prior to loss of CO2 and formation of ferrocenylamine, 78. In addition, ammonia, aniline, and ferrocenylamine react with ferrocenoyl isocyanate to yield N-ferrocenylurea, 79, N-ferrocenyl-N’-phenylurea, 80, and N,N’- diferrocenylurea, 81, respectively [48].

Inorganics 2020, 8, x FOR PEER REVIEW 12 of 22

5. Ferrocenyl Migration onto an Electron-Deficient Nitrogen Center

5.1. Beckmann Rearrangements Oximes are readily preparable by reaction of the precursor aldehyde or ketone with hydroxylamine hydrochloride [45]. When treated with reagents (e.g., H2SO4, PCl5, or SOCl2) that convert the hydroxyl into a leaving group, it brings about migration of the anti substituent to form a nitrilium ion, 70; typically, Beckmann rearrangement of the ferrocenyl oxime 71 and subsequent hydrolysis yielded the secondary amide 72 (Scheme 23) [46]. This specific geometric requirement contrasts with the situation in the pinacol rearrangement whereby the identity of the migrating group is controlled primarily by its migratory aptitude rather than its geometric alignment. Interestingly, several carbamate derivatives of ferrocenyl ketoximes have demonstrated acetylcholin-esterase activity [47].

Fc + H + H2O N Fc-N=C-R Fc-NH-C(=O)R R -H O OH 2 71 70 72 Scheme 23. Beckmann rearrangement of a ferrocenyl oxime.

While the Beckmann reaction was extensively explored in pioneering investigations by Schlögl involving a range of alkyl- or aryl-substituted ferrocenyl oximes, probably the most explicit examples are those derived from ferrocenocyclohexanones, as in Scheme 24. In these cases, the structures of the resultingInorganics 2020 ferrocenocaprolactams,, 8, 68 73 and 74, are clearly controlled by the syn or anti orientation13 of of 23 their precursor oximes [46].

OH HO O N O N H N + NH H H+ Fe Fe Fe Fe 73 74 Scheme 24. BeckmannBeckmann rearrangement rearrangement of anti and syn ferrocenocyclohexanone oximes.

5.2. Curtius Curtius Rearrangements Thermolysis of acyl azides proceeds with loss of nitrogen toto formform isocyanates.isocyanates. Although they can be isolated, the reaction is often carried out in the presence of a nucleophilic solvent such as an alcohol or amine to formform estersesters oror ureas.ureas. InIn contrastcontrast toto thethe WolWolffff rearrangement rearrangement that that can can proceed proceed via via a acarbene carbene intermediate, intermediate, the the Curtius Curtius rearrangement rearrangement is almostis almost certainly certainly a concerted a concerted process process that that does does not notinvolve involve a discrete a discrete nitrene nitrene [25]. Rearrangement [25]. Rearrangement of ferrocenoyl of ferrocenoyl azide, 75, by azide, thermolysis 75, by in thermolysis refluxing dry in refluxingtoluene furnished dry toluene ferrocenyl furnished isocyanate, ferrocenyl76. isocyanate, As shown in 76 Scheme. As shown 25, reaction in Scheme with 25, ethanol reaction or water with producesethanol or ethyl water ferrocenylcarbamate, produces ethyl ferrocenylcarbamate,77, or ferrocenylcarbamic 77, or ferrocenylcarbamic acid, prior to loss of acid, CO2 priorandformation to loss of 78 COof ferrocenylamine,2 and formation of ferrocenylamine,. In addition, ammonia, 78. In addition, aniline, ammonia, and ferrocenylamine aniline, and reactferrocenylamine with ferrocenoyl react withisocyanate ferrocenoyl to yield isocyanateN-ferrocenylurea, to yield N79-ferrocenylurea,, N-ferrocenyl- N79’-phenylurea,, N-ferrocenyl80-N,’ and-phenylurea,N,N’-diferrocenylurea, 80, and N,N’- Inorganicsdiferrocenylurea,81, respectively 2020, 8, x FOR [48 81]. PEER, respectively REVIEW [48]. 13 of 22

FcNHCH3 FcNHCO2Et LiAlH4 EtOH 77 + - Fc Cl NaN3 Fc N=N=N -N2 NH3 Fc-N=C=O FcNHC(=O)NH2 O O 75 76 79 PhNH 2 H2O FcNHCO2H FcNH2 FcNHC(=O)NHPh -CO 2 80 FcNHC(=O)NHFc 81 78 FcNH2

SchemeScheme 25. 25. CurtiusCurtius rearrangement rearrangement of of ferrocenoyl ferrocenoyl azide azide to to ferrocenyl ferrocenyl isocyanate. isocyanate.

SeveralSeveral practical practical applications applications of of this this procedure procedure have have since since been been reported. reported. Curtius Curtius rearrangement rearrangement ofof ferrocenoyl ferrocenoyl azide azide in in the the presence presence of of a a number number of of hydroxysteroids hydroxysteroids to to form form c carbamates,arbamates, such such as as 8282 (Figure(Figure 4 4),), has has been been used used in high in performancehigh performance liquid chromatography liquid chromatography using electrochemical using electrochemical detection. detection.Maximum Maximum sensitivity wassensitivity achieved was by achieved using a silver–silver by using a chloride silver–silver reference chloride electrode reference witha electrode detection withlimit of a 0.5 detection pmol. This limit derivatization of 0.5 pmol. procedure This hasderiv allowedatization the procedure facile characterization has allowed of the the products facile characterizationof the bioconversion of the of products digoxigenin of the [ 49bioconversion]. Moreover, of in digoxigenin a more recent [49] study,. Moreover, it has beenin a more shown recent that studymolecules, it has in been which shown the ferrocenyl that molecules carbamate in which unit the is linkedferrocenyl to a boroniccarbamate acid unit ester, is linked as in 83 to, a provide boronic a acidvery estesensitiver, as andin 83 rapid, provide electrochemical a very sensitive detection and technique rapid electrochemical for hydrogen peroxide detection and technique glucose; this for hydrogencan be used peroxide to follow and enzyme glucose; activity this and can cell be signaling used to follow pathways enzyme [50]. activity and cell signaling pathways [50].

O O

Me

HO Me H O O H OH N N H O H O Fe H Fe B O 82 83 O

Figure 4. Steroidal and boronic acid ester carbamates derived by reaction of alcohols with ferrocenyl isocyanate.

5.3. Benzidine Rearrangement Protonation of hydrazobenzene, 84, brings about cleavage of the HN–NH linkage and coupling of the phenyl substituents, normally in the para-positions to form 4,4’-diaminobiphenyl (benzidine), 85. In the course of their pioneering studies of derivatives of ferrocene, the Nesmeyanov group attempted the benzidine rearrangement of hydrazoferrocene, 86, but to no avail (Scheme 26). The major products arose from disproportionation to form azoferrocene, 87, and ferrocenylamine [51]. When the ferrocenyl unit was instead incorporated as a substituent in hydrazobenzene, the major products upon treatment with HCl were ferrocenylazobenzene, ferrocenylaniline, and aniline, again resulting from disproportionation rather than rearrangement [52].

Inorganics 2020, 8, x FOR PEER REVIEW 13 of 22

FcNHCH3 FcNHCO2Et LiAlH4 EtOH 77 + - Fc Cl NaN3 Fc N=N=N -N2 NH3 Fc-N=C=O FcNHC(=O)NH2 O O 75 76 79 PhNH2 H2O FcNHCO2H FcNH2 FcNHC(=O)NHPh -CO 2 80 FcNHC(=O)NHFc 81 78 FcNH2

Scheme 25. Curtius rearrangement of ferrocenoyl azide to ferrocenyl isocyanate.

Several practical applications of this procedure have since been reported. Curtius rearrangement of ferrocenoyl azide in the presence of a number of hydroxysteroids to form carbamates, such as 82 (Figure 4), has been used in high performance liquid chromatography using electrochemical detection. Maximum sensitivity was achieved by using a silver–silver chloride reference electrode with a detection limit of 0.5 pmol. This derivatization procedure has allowed the facile characterization of the products of the bioconversion of digoxigenin [49]. Moreover, in a more recent study, it has been shown that molecules in which the ferrocenyl carbamate unit is linked to a boronic acid ester, as in 83, provide a very sensitive and rapid electrochemical detection technique for

Inorganicshydrogen2020 peroxide, 8, 68 and glucose; this can be used to follow enzyme activity and cell signaling14 of 23 pathways [50].

O O

Me

HO Me H O O H OH N N H O H O Fe H Fe B O 82 83 O

Figure 4. 4. SteroidalSteroidal and and boronic boronic acid ester acid carbamates ester carbamates derived derived by reaction by reactionof alcohols of with alcohols ferrocenyl with isocyanate.ferrocenyl isocyanate.

5.3. Benzidine Rearrangement Protonation of hydrazobenzene, 84, brings about cleavage of the HN–NHHN–NH linkage and coupling of the phenyl substituents, normally in the para-positions-positions to form 4,4 4,4’-diaminobiphenyl’-diaminobiphenyl (benzidine), 85. In In the the course course of of their their pioneering pioneering studies studies of of derivatives of of ferrocene, the Nesmeyanov group attempted thethe benzidinebenzidine rearrangement rearrangement of of hydrazoferrocene, hydrazoferrocene,86, but86, but to no to avail no avail (Scheme (Scheme 26). The 26). major The productsmajor produ arosects from arose disproportionation from disproportionation to form azoferrocene,to form azoferrocene,87, and ferrocenylamine 87, and ferrocenylamine [51]. When [51] the. Whenferrocenyl the unitferrocenyl was instead unit was incorporated instead incorporated as a substituent as a in substituent hydrazobenzene, in hydrazobenzene, the major products the major upon productstreatment upon with treatment HCl were with ferrocenylazobenzene, HCl were ferrocenylazobenzene, ferrocenylaniline, ferrocenylanil and aniline,ine again, and resulting aniline, again from resultingdisproportionationInorganics 20 from20, 8, disproportionationx FOR rather PEER REVIEW than rearrangement rather than rearrangement [52]. [52]. 14 of 22

H+ N N H2N NH2 H H 85 84

H2N NH2 Fe Fe N N + Fe H H Fe H N N 86 NH2 Fe Fe + Fe 87 SchemeScheme 26.26. AttemptedAttempted benzidinebenzidine rearrangementrearrangement ofof hydrazoferrocene.hydrazoferrocene.

6.6. AnionicAnionic RearrangementsRearrangements ofof FerrocenylFerrocenyl CompoundsCompounds

6.1. Benzoins and Benzils 6.1. Benzoins and Benzils The cyanide-catalyzed condensation of aromatic aldehydes, with subsequent oxidation of the The cyanide-catalyzed condensation of aromatic aldehydes, with subsequent oxidation of the benzoin so-formed, provides a convenient route to benzils [53]. However, when starting from benzoin so-formed, provides a convenient route to benzils [53]. However, when starting from formylferrocene, this procedure failed. Moreover, the mixed benzoin condensation of benzaldehyde formylferrocene, this procedure failed. Moreover, the mixed benzoin condensation of benzaldehyde and formylferrocene yields only a single product, Ph(C=O)–CH(OH)Fc, 88 [54]. As is evident from and formylferrocene yields only a single product, Ph(C=O)–CH(OH)Fc, 88 [54]. As is evident from the mechanism shown in Scheme 27, this situation arises because nucleophilic attack by cyanide at the mechanism shown in Scheme 27, this situation arises because nucleophilic attack by cyanide at the ferrocenyl carbonyl, followed by tautomerization, would generate a carbanionic site adjacent to the ferrocenyl carbonyl, followed by tautomerization, would generate a carbanionic site adjacent to the sandwich moiety—evidently an unfavorable and unlikely circumstance. Instead, the cyanide the sandwich moiety—evidently an unfavorable and unlikely circumstance. Instead, the cyanide undergoes addition to the benzaldehyde carbonyl group. Oxidation with MnO2 yields the mixed undergoes addition to the benzaldehyde carbonyl group. Oxidation with MnO2 yields the mixed 89 benzilbenzil Fc(CFc(C=O)(C=O)Ph,=O)(C=O)Ph, 89 [[54]54]..

O- OH H KCN O HO O- O - Fc NC H Ph NC H Fc NC Ph Ph Ph H

O O O OH - O OH MnO2 -CN - Fc Fc Ph Fc Ph NC H Ph H 89 88 Scheme 27. Benzoin condensation of benzaldehyde with formylferrocene.

However, an indirect route to ferrocil (Scheme 28) was successfully achieved by Rinehart who found that the Friedel–Crafts acylation of ferrocene with the acid chloride of ferrocenylacetic acid yielded ferrocenylacetylferrocene (desoxyferrocoin), 90 [55]; subsequent oxidation with freshly prepared MnO2 furnished ferrocil, 91, in 86% yield [56].

O H O H O O ferrocene MnO2 Fc Fc Cl AlCl3 Fc Fc Fc H H 91 90 Scheme 28. Synthetic route to ferrocil.

In a modification of this approach, the Nesmeyanov group showed that the MnO2-mediated oxidation of 1,2-diferrocenylethane furnished trans-diferrocenylethene, 47, and small quantities of

Inorganics 2020, 8, x FOR PEER REVIEW 14 of 22

+ H+ N N H2N NH2 H H 2 2 H H 85 84 H N NH H2N NH2 Fe Fe N N H H H+ Fe H H Fe H N N NH 86 NH2 Fe Fe + Fe 87 87 Scheme 26. Attempted benzidine rearrangement of hydrazoferrocene.

6. Anionic Rearrangements of Ferrocenyl Compounds

6.1. Benzoins and Benzils The cyanide-catalyzed condensation of aromatic aldehydes, with subsequent oxidation of the benzoin so-formed, provides a convenient route to benzils [53]. However, when starting from formylferrocene, this procedure failed. Moreover, the mixed benzoin condensation of benzaldehyde and formylferrocene yields only a single product, Ph(C=O)–CH(OH)Fc, 88 [54]. As is evident from the mechanism shown in Scheme 27, this situation arises because nucleophilic attack by cyanide at the ferrocenyl carbonyl, followed by tautomerization, would generate a carbanionic site adjacent to the sandwich moiety—evidently an unfavorable and unlikely circumstance. Instead, the cyanide undergoes addition to the benzaldehyde carbonyl group. Oxidation with MnO2 yields the mixed Inorganicsundergoes2020 addition, 8, 68 to the benzaldehyde carbonyl group. Oxidation with MnO2 yields the mixed15 of 23 benzil Fc(C=O)(C=O)Ph, 89 [54].

O O- OH H KCN O HO O- O O - Fc Ph NC H Ph NC H Fc NC Ph Ph Ph Ph H

OH - O O O MnO O OH - O- OH MnO2 -CN - Fc Fc NC Fc Ph Fc Ph NC Ph Fc H H Ph H 89 88 88 Scheme 27. Benzoin condensation of benzaldehyde with formylferrocene.

However, anan indirect indirect route route to to ferrocil ferrocil (Scheme (Scheme 28) was28) was successfully successfully achieved achieved by Rinehart by Rinehart who found who thatfound the tha Friedel–Craftst the Friedel– acylationCrafts acylation of ferrocene of ferrocene with the with acid the chloride acid chloride of ferrocenylacetic of ferrocenylacetic acid yielded acid ferrocenylacetylferroceneyielded ferrocenylacetylferrocene (desoxyferrocoin), (desoxyferrocoin),90 [55]; subsequent 90 [55]; oxidation subsequent with oxidation freshly prepared with freshly MnO2 furnished ferrocil, 91, in 86% yield [56]. prepared MnO2 furnished ferrocil, 91, in 86% yield [56].

O H O H O O O ferrocene O H MnO O O ferrocene MnO2 Fc AlCl Fc Cl AlCl3 Fc Fc Fc H H 90 91 90 Scheme 28.28. Synthetic route to ferrocil.

InorganicsInIn a a20 modificationmodification20, 8, x FOR PEER ofof REVIEW thisthis approach,approach, thethe NesmeyanovNesmeyanov groupgroup showedshowed thatthat thethe MnOMnO22-mediated-mediated15 of 22 oxidation of 1,2-diferrocenylethane1,2-diferrocenylethane furnished transtrans-diferrocenylethene,-diferrocenylethene, 47, and smallsmall quantitiesquantities ofof ferrocil.ferrocil. Satisfyingly, furtherfurther oxidationoxidation ofof thethe alkenealkene gavegave 91 in 40% yield [57] [57].. Unsurprisingly, Unsurprisingly, ferrocil does not undergo the benzil-to-benzilicbenzil-to-benzilic acid rearrangement; once again, such a process would have required thethe migrationmigration ofof aa ferrocenylferrocenyl unitunit underunder electronicallyelectronically unfavorableunfavorable anionicanionic conditions.conditions. The ready availabilityavailability of thethe mixedmixed benzilsbenzils 1-ferrocenyl-2-aryl-1,2-dioxoethane,1-ferrocenyl-2-aryl-1,2-dioxoethane, 89 and 92,, hashas been shown to provide provide a a convenient convenient route route to to ferrocenyl-triaryl-cyclopentadienones, ferrocenyl-triaryl-cyclopentadienones, 93 that are are versatile precursorsprecursors to to the the sterically sterically hindered hindered arenes arenes C6 RC56Fc,R5Fc, where where R = Rphenyl = phenyl or βor-naphthyl, β-naphthyl, and and the cycloheptatrienethe cycloheptatriene C7Ph C67PhHFc6HFc (Scheme (Scheme 29)[ 29)54 ,[54,58,59]58,59]. .

O Ar O O Ar Ar Ar Ar

Fc O KOH Ph Fc Ar 89 Ar = phenyl 93 Ar = naphthyl Ph 92 Ar Ar Ph - CO H

Ar Ph Ph Ar Ar Ph H Fc Fc Ar Ph Ar Ph Ph Scheme 29. Synthetic routes to poly-arylatedpoly-arylated benzenes and cycloheptatrienes.

6.2. Stevens Rearrangement In a conventional Stevens rearrangement, deprotonation of a quaternary ammonium salt generates an ylid whereby one of the substituents undergoes migration from nitrogen. Typically, as shown in Scheme 30, under these conditions the benzyltrimethylammonium salt, 94, is converted to 2-methylbenzyldimethylamine, 95. In contrast, upon methylation to form 96, N,N-dimethyl- aminomethylferrocene undergoes a quite different isomerization process to generate N,N- dimethylaminoethylferrocene, 97 [60]. This may be rationalized on the basis that, as noted in Section 6.1, the ferrocenyl moiety is less willing than phenyl to tolerate negative charge. We note, however, that more recently, it has been suggested that the mechanism of the Stevens rearrangement may actually involve radical coupling within a solvent cage [61].

CH3 CH3 - CH2 NaNH2 + + H2C N H2C N H C N CH3 CH3 2 CH3

94 CH3 CH3 95 CH3

- CH2 Fc CH3 Fc H2 NaNH2 Fc + + C H2C N H2C N C N CH3 CH3 CH3 H2

CH3 CH3 CH 96 97 3 Scheme 30. Different Stevens rearrangements for analogous phenyl and ferrocenyl structures.

7. Ferrocenes in Bioorganometallic Chemistry

7.1. Quinone Methides Bioorganometallic chemistry, a neologism introduced by a small group of us in the mid-1980s [62,63], focuses on the bioactivity of complexes possessing at least one metal-carbon bond. It was

Inorganics 2020, 8, x FOR PEER REVIEW 15 of 22

ferrocil. Satisfyingly, further oxidation of the alkene gave 91 in 40% yield [57]. Unsurprisingly, ferrocil does not undergo the benzil-to-benzilic acid rearrangement; once again, such a process would have required the migration of a ferrocenyl unit under electronically unfavorable anionic conditions. The ready availability of the mixed benzils 1-ferrocenyl-2-aryl-1,2-dioxoethane, 89 and 92, has been shown to provide a convenient route to ferrocenyl-triaryl-cyclopentadienones, 93 that are versatile precursors to the sterically hindered arenes C6R5Fc, where R = phenyl or β-naphthyl, and the cycloheptatriene C7Ph6HFc (Scheme 29) [54,58,59].

O Ar O O Ar Ar Ar Ar

Fc O KOH Ph Fc Ar 89 Ar = phenyl 93 Ar = naphthyl Ph 92 Ar Ar Ph - CO H

Ar Ph Ph Ar Ar Ph H Fc Fc Ar Ph Ar Ph Ph Inorganics 2020, 8, 68 16 of 23 Scheme 29. Synthetic routes to poly-arylated benzenes and cycloheptatrienes. 6.2. Stevens Rearrangement 6.2. Stevens Rearrangement In a conventional Stevens rearrangement, deprotonation of a quaternary ammonium salt In a conventional Stevens rearrangement, deprotonation of a quaternary ammonium salt generates an ylid whereby one of the substituents undergoes migration from nitrogen. Typically, generates an ylid whereby one of the substituents undergoes migration from nitrogen. Typically, as as shown in Scheme 30, under these conditions the benzyltrimethylammonium salt, 94, is shown in Scheme 30, under these conditions the benzyltrimethylammonium salt, 94, is converted to converted to 2-methylbenzyldimethylamine, 95. In contrast, upon methylation to form 96, 2-methylbenzyldimethylamine, 95. In contrast, upon methylation to form 96, N,N-dimethyl- N,N-dimethyl-aminomethylferrocene undergoes a quite different isomerization process to generate aminomethylferrocene undergoes a quite different isomerization process to generate N,N- N,N-dimethylaminoethylferrocene, 97 [60]. This may be rationalized on the basis that, as noted in dimethylaminoethylferrocene, 97 [60]. This may be rationalized on the basis that, as noted in Section Section 6.1, the ferrocenyl moiety is less willing than phenyl to tolerate negative charge. We note, 6.1, the ferrocenyl moiety is less willing than phenyl to tolerate negative charge. We note, however, however, that more recently, it has been suggested that the mechanism of the Stevens rearrangement that more recently, it has been suggested that the mechanism of the Stevens rearrangement may may actually involve radical coupling within a solvent cage [61]. actually involve radical coupling within a solvent cage [61].

CH3 CH3 - CH2 NaNH2 + + H2C N H2C N H C N CH3 CH3 2 CH3

94 CH3 CH3 95 CH3

- CH2 Fc CH3 Fc H2 NaNH2 Fc + + C H2C N H2C N C N CH3 CH3 CH3 H2

CH3 CH3 CH 96 97 3 SchemeScheme 30.30. DiDifferentfferent StevensStevens rearrangementsrearrangements forfor analogousanalogous phenylphenyl andand ferrocenylferrocenyl structures.structures.

7.7. FerrocenesFerrocenes inin BioorganometallicBioorganometallic ChemistryChemistry

7.1. Quinone Methides 7.1. Quinone Methides Bioorganometallic chemistry, a neologism introduced by a small group of us in the mid-1980s [62, Bioorganometallic chemistry, a neologism introduced by a small group of us in the mid-1980s 63], focuses on the bioactivity of complexes possessing at least one metal-carbon bond. It was developed [62,63], focuses on the bioactivity of complexes possessing at least one metal-carbon bond. It was to extend the range and efficacy of metal-based systems beyond that of the widely-used platinum drugs. Although many transition-metal complexes have been studied, ferrocifens, the ferrocenyl analogues of tamoxifen, the current first-line treatment of hormone-dependent breast cancers, whereby a phenyl has been replaced by ferrocenyl, have proved particularly successful against both hormone-dependent and hormone-independent tumors [64]. Their activity is predicated on the reversible redox activity of the ferrocenyl moiety that mediates conversion of ferrociphenols, 98, into the corresponding quinone methides, 99, that undergo Michael additions with thiols or selenols of key proteins crucial to maintaining redox balance in the cell [65–67]. The net result is to inhibit the regeneration of thioredoxin that defends the cell from attack by reactive oxygen species (ROS), such as hydroxyl radicals. The mode of action of thioredoxin is to trap the ROS by abstraction of hydrogen from its vicinal cysteine thiols, which then form disulfides, a process reversible only by thioredoxin reductase in conjunction with NADPH [67]. Generation of these quinone methides can also be accomplished in vitro by chemical oxidation of ferrociphenols with silver oxide, or enzymatically by using horseradish peroxidase (HRP/H2O2), as depicted in Scheme 31. InorganicsInorganics 20202020,, 88,, xx FORFOR PEERPEER REVIEWREVIEW 1616 of 2222 developed to extend the range and efficacy of metal--based systems beyond that of the widely--used platinum drugs. Although many transition--metal complexes have been studied, ferrocifensferrocifens,, the the ferrocenylferrocenyl analogues analogues of of tamoxifentamoxifen,, the the current current first first--lineline treatment treatment of of hormone hormone--dependent breast cancers, whereby a phenyl has been replacedreplaced by by ferrocenyl, ferrocenyl, have have proved proved particularly particularly successful successful against both hormone--dependent and hormone--independentindependent tumotumorrs [64][64].. Their activity is predicated on the reversible redox activity of the ferrocenyl moiety that mediates conversion of ferrociphenols, 98,, intointo thethe correspondingcorresponding quinonequinone methides,methides, 99,, thatthat undergoundergo MichaelMichael additions with thiols or selenols of key proteins crucial to maintaining redox balance in the cell [65[65– 67].. TheThe netnet resultresult isis toto inhibitinhibit thethe regenerationregeneration ofof thioredoxinthioredoxin thatthat defendsdefends tthe cell from attack by reactivereactive oxygenoxygen speciesspecies (ROS),(ROS), suchsuch asas hydroxylhydroxyl radicals.radicals. TheThe modemode ofof actionaction ofof thioredoxinthioredoxin isis toto traptrap thethe ROSROS byby abstractionabstraction ofof hydrogenhydrogen fromfrom itsits vicinalvicinal cysteinecysteine thiols,thiols, whichwhich thenthen formform disulfides,disulfides, aa process reversible only by thioredoxinredoxin reductasereductase inin conjunctionconjunction withwith NADPHNADPH [67][67].. GenerationGeneration ofof thesethese quinonequinone methidesmethides cancan alsoalso bebe accomplishedaccomplished inin vitrovitro by chemical oxidation of ferrociphenols Inorganicswith silver2020 , oxide,8, 68 or enzymatically by using horseradish peroxidase (HRP/H22O22),), as as depicted depicted17 of in23 in Scheme 31.

OH O

Ag2O orr Fe 2 Fe HRP / H O HRP / H22O22

R = H, OH or R R = H, OH or R 98 O((CH2))nNMe2 99 n 2 SchemeScheme 31.31. Chemical or enzymatic conversionconversion ofof ferrociphenolsferrociphenols intointo quinonequinone methides.methides.

7.2.7.2. Formation of Indenes TheThe rearrangementrearrangement behaviorbehavior ofof thesethese bioactivebioactive ferrocenyl-containingferrocenyl--containing molecules parallels that ofof thethethe moremore conventionalconventional systemssystems discusseddiscussed already.already. ProtonationProtonation ofofof ferrocenylferrocenyl quinonequinonequinone methidesmethides bringsbrings aboutabout rearomatizationrearomatization ofof thethe quinonequinone ringring andand initiallyinitially generates a doubly doubly-benzylic--benzylic carbocation, 100,, thatthatthat readilyreadilyreadily cyclizescyclizescyclizes sososo asasas tototo placeplaceplace thethethe electronelectronelectron deficiencydeficiencydeficiency adjacentadjacentadjacent tototo thethethe ferrocenylferrocenylferrocenyl substituent,substituent,substituent, asasas ininin 101101,,, leading leading leading ultimately ultimately ultimately to to formationto formation formation of indene of of indene indene102 (Scheme 102 (Scheme(Scheme 32)[68 32) 32)], entirely [68][68],, entirely entirely analogous analogous analogous to the reactions to to the the describedreactionsreactions describeddescribed in Section inin2.2 SectionSection. 2.2.2.2.

OH OH OH + H++ H + ++ 99 Fe + Fe --H Fe R = H,, OH orr O(CH2) NMe O(CH2)nnNMe22 100 R 101 R 102 R R 101 R 102 R SchemeScheme 32.32. Protonation of aa ferrocenylferrocenyl quinonequinone methidemethide leadsleads toto formationformation ofof indenes.indenes.

7.3.7.3. Formation and RearrangementRearrangement ofof aa Ferrocenyl-TetrahydrofuranylFerrocenyl--Tetrahydrofuranyl QuinoneQuinone MethideMethide AA particularlyparticularly interestinginteresting transformationtransformation occursoccurs inin thethe enzymaticenzymatic oror chemicalchemical oxidation ofof thethe hydroxypropyl-ferrociphenol,hydroxypropyl--ferrociphenol,ferrociphenol,103 103, that,, yields, that that yields, yields, among other among among products, other other a spiro-bonded products, products, a a tetrahydrofuran spiro spiro--bonded derivative,tetrahydrofurantetrahydrofuran104 (Scheme derivative, derivative, 33). When 104 (Scheme(Scheme protonated, 33). 33). this When When molecule protonated, protonated, undergoes this this both molecule molecule ferrocenyl undergoes undergoes migration both both and ringferrocenylferrocenyl expansion migrationmigration to yield andand the ringring dihydrofuran, expansionexpansion105 toto ,yieldyield and the thethe dihydropyran, didihydrofuran,106 105,,, respectively andand thethe dihydropyran,dihydropyran, (Scheme 34)[ 10665].,, TheirInorganicsrespectivelyrespectively X-ray 2020 crystal, (Scheme8(Scheme, x FOR structures PEER 34)34) REVIEW[65][65]..are TheirTheir shown XX--rayray as crystalcrystal Figure 5structuresstructures. areare shownshown asas FigureFigure 5.5. 17 of 22

OH OH

OH O O O + Ag2O or -H+ Fe Fe Fe HRP/H2O2

103 OH OH OH 104 Scheme 33. 33. Chemical or enzymatic oxidation of the hydroxypropyl-ferrociphenol,hydroxypropyl-ferrociphenol, 103, yields yields the the tetrahydrofuranyl-quinonetetrahydrofuranyl-quinone methide, 104104..

O OH O O O + 1N HCl + OH Fe Fe Fe acetone OH 104 OH OH - H+

OH OH O O - H+ + O OH Fe Fe Fe OH OH 105 106 OH Scheme 34. Ferrocenyl migration and ring expansion upon protonation of the tetrahydrofuranyl- quinone methide, 104.

Figure 5. Molecular structures of (left) dihydrofuran, 105, and (right) dihydropyran, 106.

7.4. Pinacol-to-Pinacolone Rearrangement of Ansa-Ferrociphenols In yet another example in the bioorganometallic arena, the synthesis of an ansa-ferrociphenol from [3]ferrocenophanone, 107, by McMurry coupling yields not only the desired alkene, 108, but also the corresponding pinacolone, 109, (Scheme 35) both of whose X-ray crystal structures are shown as Figure 6.

InorganicsInorganics 20 202020, ,8 8, ,x x FOR FOR PEER PEER REVIEW REVIEW 1717 of of 22 22

OOHH OOHH OH O OH O OO ++ OO Ag2O or + Ag2O or --HH+ Fe Fe Fe Fe FFee HRP/H2O2 HRP/H2O2 OH OH 110033 OH OH 104 OOHH 104 Scheme 33. Chemical or enzymatic oxidation of the hydroxypropyl-ferrociphenol, 103, yields the InorganicsScheme2020, 8 33., 68 Chemical or enzymatic oxidation of the hydroxypropyl-ferrociphenol, 103, yields th18e of 23 tetrahydrotetrahydrofuranylfuranyl--quinonequinone methide, methide, 104 104. .

OO OOHH O O O ++ O O O+ OH 11NN H HCCll + OH FFee FFee FFee aacceetotonnee OOHH 110044 OOHH OOHH + - -H H+

OOHH OOHH OO OO + + O - -H H+ + O OOHH Fe Fe Fe Fe FFee OOHH OOHH 110055 OH 110066 OH SchemeScheme 34. 34. FerrocenylFerrocenylFerrocenyl migration migration and and ring ring ring expansion expansion expansion upon upon upon protonation protonationprotonation of of of the the the tetrahydrofuranyl tetrahydrofuranyl- tetrahydrofuranyl-- quinonequinone methide, methide, 104 104. .

Figure 5. Molecular structures of (left) dihydrofuran, 105, and (right) dihydropyran, 106. FigureFigure 5. 5. Molecular Molecular structures structures of of (left) (left) dihydrofuran, dihydrofuran, 105 105, ,and and (right) (right) dihydropyran, dihydropyran, 106 106. . 7.4. Pinacol-to-Pinacolone Rearrangement of Ansa-Ferrociphenols 7.4.7.4. Pinacol Pinacol--toto--PinacolonePinacolone Rearrangement Rearrangement of of Ansa Ansa--FerrociphenolsFerrociphenols In yet another example in the bioorganometallic arena, the synthesis of an ansa-ferrociphenol In yet another example in the bioorganometallic arena, the synthesis of an ansa-ferrociphenol fromIn [3]ferrocenophanone, yet another example107 in, bythe McMurry bioorganometallic coupling yields arena, not the only synthesis the desired of an alkene, ansa-ferrociphenol108, but also from [3]ferrocenophanone, 107, by McMurry coupling yields not only the desired alkene, 108, but fromthe corresponding [3]ferrocenophanone, pinacolone, 107109, by, (SchemeMcMurry 35 coupling) both of yields whose not X-ray onl crystaly the desired structures alkene, are shown 108, but as alsoalso the the corresponding corresponding pinacolone, pinacolone, 109 109, ,(Scheme (Scheme 35) 35) both both of of whose whose X X--rayray crystal crystal structures structures are are shown shown FigureInorganics6. 2020, 8, x FOR PEER REVIEW 18 of 22 asas Figure Figure 6. 6. HO O OH O OH

Fe Zn, TiCl + Fe O 4 Fe pyridine

107 108 109 Scheme 35. Pinacol rearrangement of a [3]ferrocenophanone.[3]ferrocenophanone.

Figure 6. Molecular structures of the ansa-ferrociphenol, 108, and the pinacolone, 109.

In this case, there are two possible pinacolones: one derived by cation formation adjacent to the ferrocenyl group, as in 110, the other at the doubly-benzylic position, 111, as illustrated in Scheme 36. In the event it is the latter that succeeds, it is presumably to relieve the ring strain in the three-carbon bridge thereby forming the pinacolone possessing a four-carbon link between the cyclopentadienyl rings [69]. Moreover, in this strained system, the potential carbocation, 110, adjacent to ferrocene, is unable to enhance its stability by bending towards the metal.

Ar OH O Ar Ar + Ar Fe Fe 110 Ar OH Ar Ar OH Fe + Ar Ar Ar OH Fe Fe O

111 Scheme 36. Carbocation formation at a doubly-benzylic site, rather that adjacent to ansa-ferrocenyl.

8. Concluding Comments The remarkable ability of the ferrocenyl moiety to stabilize a neighboring carbocationic site manifests itself in a number of ways. In some cases, such as [(C5H5)Fe(C5H4-CPh2][BF4], the species is sufficiently stable to be isolated and structurally characterized by X-ray crystallography. In others, it directs the course of an isomerization or migration by stabilizing a transition state or intermediate by alleviating the electron deficiency and tolerating any excess positive charge on the iron atom.

InorganicsInorganics 20202020,, 88,, xx FORFOR PEERPEER REVIEWREVIEW 1818 ofof 2222

HHOO OO OOHH OO OOHH

Fe + O Fe ZZnn,, TTiiCCll4 + FFee O 4 FFee ppyyrriiddiinnee 107 108 109 107 108 109 Inorganics 2020, 8, 68 19 of 23 SchemeScheme 35.35. PinacolPinacol rearrangementrearrangement ofof aa [3][3]ferrocenophanone.ferrocenophanone.

FigureFigure 6.6. MolecularMolecular structures structures of of the the ansaansa--ferrociphenol,-ferrociphenol,ferrociphenol, 108108,, and and the the pinacolone, pinacolone, 109109..

InIn this this case, case, there there areare twotwo possiblepossible pinacolones:pinacolones: one one derived derived by by cation cation formation formation adjacent adjacent to to the the ferrocenylferrocenyl group,group, asas inin 110110,, the thethe other otherother at atat the thethe doubly doubly-benzylicdoubly--benzylicbenzylic position, position, 111111,,, as as illustrated illustrated in in SchemeScheme 36.36.36. InIn the the event event it it is is the the latter latter that that succeeds, succeeds, it it is isis presumablypresumably to to relieve relieve the the ring ring strain strain in in the the three three-carbonthree--carboncarbon bridgebridge thereby thereby formingforming thethe pinacolonepinacolone possessingpossessing a a four-carbonfourfour--carboncarbon linklink betweenbetween thethe cyclopentadienylcyclopentacyclopentadienyldienyl ringsrings [69] [[69]69]... Moreover,Moreover, Moreover, inin in thisthis this strainedstrained strained system,system, system, thethe the potentialpotential potential carbocation,carbocation, carbocation, 110110110,, adjacentadjacent, adjacent toto toferrocene,ferrocene, ferrocene, isis unableisunable unable toto toenhanceenhance enhance itsits its stabilitystability stability byby by bendingbending bending towardstowards towards thethe the metal.metal. metal.

AArr OOHH OO AArr + AArr + AArr FFee FFee 111100 AArr OOHH AArr AArr OOHH + FFee + Ar AArr Ar AArr OH Fe OH O Fe FFee O 111 111 Scheme 36. ansa SchemeScheme 36.36. CarbocationCarbocation formation formation at at a a doubly doubly-benzylicdoubly--benzylicbenzylic site, site, rather rather thatthat adjacenadjacentadjacentt toto ansaansa--ferrocenyl.-ferrocenyl.ferrocenyl. 8. Concluding Comments 8.8. ConcludingConcluding CommentsComments The remarkable ability of the ferrocenyl moiety to stabilize a neighboring carbocationic site TheThe remarkable remarkable ability ability of of the the ferrocenyl ferrocenyl moiety moiety to to stabilize stabilize a a neighboring neighboring carbocationic carbocationic site site manifests itself in a number of ways. In some cases, such as [(C5H5)Fe(C5H4-CPh2][BF4], the species is manifests itself in a number of ways. In some cases, such as [(C5H5)Fe(C5H4-CPh2][BF4], the species is sumanifestsfficiently itself stable in a to number be isolated of ways. and structurallyIn some cases, characterized such as [(C5H by5)Fe(C X-ray5H crystallography.4-CPh2][BF4], the Inspecies others, is sufficiently stable to be isolated and structurally characterized by X-ray crystallography. In others, it itsufficiently directs the s coursetable to of be an isolated isomerization and structurally or migration characterized by stabilizing by aX transition-ray crystallography. state or intermediate In others, by it directs the course of an isomerization or migration by stabilizing a transition state or intermediate by alleviatingdirects the thecourse electron of an deficiencyisomerization and or tolerating migration any by excess stabilizing positive a transition charge on state the or iron intermediate atom. by alleviating the electron deficiency and tolerating any excess positive charge on the iron atom. alleviatingIt is particularly the electron gratifying deficiency that and the tolerating incorporation any exce ofss ferrocenyl positive charge units intoon the bioactive iron atom. materials has been so successful. We have already discussed its role in enhancing the efficacy and range of applicability of tamoxifen by replacing a phenyl substituent by ferrocenyl in the ferrocifens for the treatment of a broad range of cancers [63]. Another spectacular advance has been the adoption of ferroquine as a replacement for chloroquine in the world-wide fight against malaria [70]. It is evident that the electronic control exerted by the ferrocenyl group continues to attract attention, and will undoubtedly lead to additional practical applications.

Funding: For those sections concerning our own work, this research was funded for many years by the Natural Sciences and Engineering Research Council of Canada (NSERC), the Petroleum Research Fund (PRF), administered by the American Chemical Society, and by Science Foundation Ireland (SFI). Inorganics 2020, 8, 68 20 of 23

Acknowledgments: The author thanks University College Dublin and the UCD School of Chemistry for additional financial support, and the Centre for Synthesis and Chemical Biology (CSCB) for the use of analytical facilities. He also thanks his long-time French colleagues Anne Vessières and Gérard Jaouen for many valuable discussions, and the reviewers for their helpful and constructive comments. Conflicts of Interest: The author declares no conflict of interest.

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