Rollover Cyclometalation As a Valuable Tool for Regioselective C–H Bond Activation and Functionalization

molecules

Review Rollover Cyclometalation as a Valuable Tool for Regioselective C–H Bond Activation and Functionalization

Antonio Zucca * and Maria I. Pilo

Department of Chemistry and Pharmacy, University of Sassari, via Vienna 2, 07100 Sassari, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-079229493

Abstract: Rollover cyclometalation constitutes a particular case of cyclometallation reaction. This reaction occurs when a chelated heterocyclic ligand loses its bidentate coordination mode and undergoes an internal rotation, after which a remote C–H bond is regioselectively activated, affording an uncommon cyclometalated complex, called “rollover cyclometalated complex”. The key of the process is the internal rotation of the ligand, which occurs before the C–H bond activation and releases from coordination a donor atom. The new “rollover” ligand has peculiar properties, being a ligand with multiple personalities, no more a spectator in the reactivity of the complex. The main reason of this peculiarity is the presence of an uncoordinated donor atom (the one initially involved in the chelation), able to promote a series of reactions not available for classic cyclometalated complexes. The rollover reaction is highly regioselective, because the activated C–H bond is usually in a symmetric position with respect to the donor atom which detaches from the metal stating the rollover process. Due to this novel behavior, a series of potential applications have appeared in the literature, in ﬁelds such as catalysis, organic synthesis, and advanced materials.

Keywords: rollover cyclometalation; C–H bond activation; C–H bond functionalization

Citation: Zucca, A.; Pilo, M.I. Rollover Cyclometalation as a Valuable Tool for Regioselective C–H 1. Introduction Bond Activation and Metal-mediated activation and functionalization of C–H bonds are fundamental topics Functionalization. Molecules 2021, 26, in organometallic chemistry. Several efforts have been done in the past decades to shed 328. https://doi.org/10.3390/ light onto the mechanisms implied in the process. The intramolecular version of C–H molecules26020328 bond activation, i.e., cyclometalation [1], has been extensively studied in recent decades for

Academic Editor: several reasons: the reaction is easier to study than the analogous inter-molecular counter- Patricia Garcia-Garcia part, but occurs with comparable mechanisms; the products of the reactions, the so-called Received: 7 December 2020 cyclometalated complexes, possess an additional stability due to chelated effect and have Accepted: 4 January 2021 shown an ample spectrum of potential applications in different fields, from homogeneous Published: 10 January 2021 catalysis to advanced materials and biomedicine. Worth of note, the cyclometalation reaction is usually highly regioselective, as, for example, in the case of ortho-metalation. Publisher’s Note: MDPI stays neu- In cyclometalation, the C–H bond activation is usually a heteroatom-assisted process, tral with regard to jurisdictional clai- involving classical donors such as N, O, P, S, even though also C-assisted cyclometalations ms in published maps and institutio- are known. The initial coordination of the donor atom holds the C–H bond close to nal affiliations. metal, facilitating its activation. As a consequence, the classical cyclometalation pathway generally consists of two consecutive steps: (i) initial coordination of a donor atom and (ii) subsequent intramolecular activation of a C–H bond to form a metallacycle [2]. Closely related to cyclometalation is the directed ortho-metalation [3], where regioselective ortho Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. C–H bond activation is heteroatom-assisted; in this case, however, the metallacycle is not This article is an open access article preserved due to the nature of the heteroatom-metal bond. distributed under the terms and con- The first cyclometalation reaction appeared in 1955, described as an “aluminum ditions of the Creative Commons At- organometallic inner complex” [4], but the term “cyclometalation” was coined only in 1973 tribution (CC BY) license (https:// by Trofimenko [5]. creativecommons.org/licenses/by/ The properties of cyclometalated complexes may be tuned in a number of ways. In 4.0/). these species, the correlation between ligands and complexes properties can be remarkably

Molecules 2021, 26, 328. https://doi.org/10.3390/molecules26020328 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 59

The first cyclometalation reaction appeared in 1955, described as an “aluminum organometallic inner complex”[4], but the term “cyclometalation” was coined only in 1973 Molecules 2021, 26, 328 by Trofimenko [5]. 2 of 58 The properties of cyclometalated complexes may be tuned in a number of ways. In these species, the correlation between ligands and complexes properties can be remarka- blyhigh, high, so thatso that modification modification of the of the stereoelectronic stereoelectronic parameters parameters of theof the cyclometalated cyclometalated ligand lig- andusually usually allows allows a refined a refine tuningd tuning of the of overallthe overall properties properties of the of complex. the complex. InIn addition to classical cyclometalated complexes, a a series of variations on the basic themetheme leadlead toto several several subclasses, subclasses, such such as thatas that of the of so-calledthe so-called “pincer” “pincer” complexes complexes [6], where [6], wherethe metallacycle the metallacycle is comprised is comprised in a tridentate in a tridentate system (e.g., system NˆCˆN (e.g., or CˆNˆC).N^C^N A or less-common C^N^C). A less-commonspecial class of special cyclometalated class of cyclometalated species, the so-called species, “rollover” the so-called complexes “rollover” [7], has complexes assumed [7],a particular has assumed interest a particular in recent years,interest having in recent peculiar years, properties having peculiar that distinguish properties it fromthat dis- the tinguishother cases. it from the other cases. Consequently, thethe reactionreaction whichwhich leads leads to to these these compounds, compounds, i.e., i.e., rollover rollover cyclometala- cyclomet- alation,tion, has has attracted attracted attention. attention. In rollover In rollover metalation, metalation, a chelated a chelated ligand, ligand, usually usually a heteroaro- a het- eroaromaticmatic bidentate bidentate donor donor such assuch 2,2 as0-bipyridine, 2,2’-bipyridine, may may choose choose to coordinate to coordinate in the in classicalthe clas- sicalway, way, i.e., asi.e., a as chelated a chelated ligand, ligand, or, or, after after internal internal rotation rotation and and deprotonation, deprotonation, asas an N^C NˆC anionic cyclometalated ligand. The key of of the the pr processocess is is the the internal internal rotation rotation of of the the ligand, ligand, which allows activation of a C–HC−H bond initially distant from the metal. Taking 2,2’-bipyridine 2,20-bipyridine as as a a model, model, roll-over roll-over cyclometalation cyclometalation follows follows a aseries series of of ele- el- mentaryementary steps steps (Figure (Figure 1):1 ):First, First, the the ligand ligand will will behave behave as a as classical a classical N^N NˆN chelate chelate (A), then (A), onethen of one the of nitrogen the nitrogen donors donors decoordinates decoordinates (B), allowing (B), allowing rotation rotation along the along C–C the bond C–C which bond connectswhich connects the two the heteroaromatic two heteroaromatic rings rings(C). The (C). internal The internal rotation rotation allows allows activation activation of the of initiallythe initially remote remote C(3)-H C(3)-H bond bond (D), to (D), afford to afford the final the finalcyclometalated cyclometalated product product (E). The (E). reac- The tionreaction is highly is highly regioselective, regioselective, because because it allows it allows activation activation of a C–H of a C–Hbond bond on the on other the other side withside withrespect respect to the to detached the detached nitrogen, nitrogen, usually, usually, as in as this in thiscase, case, in a insymmetric a symmetric position. position.

FigureFigure 1. Rollover 1. Rollover cyclometalation: cyclometalation: fundamental fundamental steps. steps.

ItIt is is important, important, for for a a “true” “true” rollover rollover cyclometalation, cyclometalation, to start from from a chelated chelated complex complex fromfrom which which C–H C–H bond bond activation activation occurs occurs in in a a succeeding succeeding coordinatively coordinatively unsaturated unsaturated com- com- plex. In In their their review review of of 201 201 [7], [7], Butschke Butschke an andd Schwarz Schwarz coined coined the the term term “pseudo-rollover” “pseudo-rollover” cyclometalation, for for those those cases cases that that proceed proceed in in a a mechanistically different different mode, mode, for for inin- stance, starting starting from from a amonodentate monodentate complex, complex, without without chelation; chelation; in this in this case, case, a simple a simple cyclometalationcyclometalation occurs, occurs, but but the the final final complex complex may may be bealso also classified classified as a as rollover a rollover species. species. In otherIn other cases cases of ofpseudo-rollover pseudo-rollover cyclometalation, cyclometalation, the the ligand ligand has has been been previously previously activated, activated, e.g., by lithiation or other methods. Several studies have been made in order to elucidate the mechanism of the rollover process. The The final final step, i.e., metal-mediated C–H C–H activation, activation, can can follow follow different different mecha- mecha- nisms depending on the metal involved and the rollover ligand implied. This aspect will nisms depending on the metal involved and the rollover ligand implied. This aspect will be treated in Section3. be treated in Section 3. Even though 2,20-bipyridines have initially been the most studied ligands in this Even though 2,2’-bipyridines have initially been the most studied ligands in this field, the reaction is not restricted to these family of compounds and interests a vast series field, the reaction is not restricted to these family of compounds and interests a vast series of heteroaromatic compounds. As a general rule, every bidentate heterocyclic ligand of heteroaromatic compounds. As a general rule, every bidentate heterocyclic ligand hav- having a C–H bond in a symmetric position to one of the donor atoms, flexible enough to ing a C–H bond in a symmetric position to one of the donor atoms, flexible enough to allow internal rotation, can potentially give rollover cyclometalation. Ligands without this allow internal rotation, can potentially give rollover cyclometalation. Ligands without this symmetry are also able to follow a rollover pathway, provided the presence of an available C–H bond “on the other side”. In Figure2, we report a selection of rollover complexes derived from 2,2 0-bipyridines (A), 2-(2-thienyl)pyridine (B), 2-(1-pyrazolyl)pyridine (C), 1-(2-thienyl)-1H-pyrazole (D), pyrazolylmethanes (E), 2-phenyl-pyridine (F). The last example, G, derived from N-(20- Molecules 2021, 26, x FOR PEER REVIEW 3 of 59

symmetry are also able to follow a rollover pathway, provided the presence of an available C–H bond “on the other side”. Molecules 2021, 26, 328 3 of 58 In Figure 2, we report a selection of rollover complexes derived from 2,2’-bipyridines (A), 2-(2-thienyl)pyridine (B), 2-(1-pyrazolyl)pyridine (C), 1-(2-thienyl)-1H-pyrazole (D), pyrazolylmethanes (E), 2-phenyl-pyridine (F). The last example, G, derived from N-(2’- pyridyl)-7-azaindole,pyridyl)-7-azaindole, is is a a case case of a rolloverrollover complexcomplex without without the the above-mentioned above-mentioned N/C– N/C– HH symmetry. symmetry.

Figure 2. SelectionFigure of 2. rolloverSelection complexes. of rollover complexes.

HavingHaving defined defined reaction reaction and and ligands, ligands, some some considerations considerations follow, follow, considering considering a age- nericgeneric E, E E,chelating E chelating ligand ligand (E (E= N, = N,S, O, S, O,etc.): etc.): • roll-over cyclometalation is favored by the presence of one weak M–E bond in the • roll-over cyclometalation is favored by the presence of one weak M–E bond in the starting chelated complex. The weakness may be related to steric or electronic factors: starting chelated complex. The weakness may be related to steric or electronic factors: as a consequence, the reaction will be favored by bulky substituents in adjacent asposition a consequence, to E, electron-withdrawing the reaction will be groups favored in the by ring bulky and substituen ligands withts in strong adjacenttrans po-- sitioninfluence to E, coordinated electron-withdrawing in trans to E. Transgroups-influence in the ring and transand -effectligands may with have strong dramatic trans- influenceeffect on coordinated the behavior ofin sometrans ligandsto E. Trans and-influence in catalytic and applications; trans-effect may have dra- • maticformation effect ofon a the strong behavior M–C bondof some will ligands thermodynamically and in catalytic favor applications; the rollover process • formationtoward classic of a strong chelation. M–C For bond this will reason, thermodynamically late and heavy transition favor the metalsrollover such process as towardiridium classic and platinum chelation. are For favored; this reason, late and heavy transition metals such as • iridiuma second and peculiarity platinum ofare rollover favored; cyclometalation is found in the mechanism of the • a cyclometalationsecond peculiarity reaction: of rollover in the stepcyclometalation from chelate tois monodentatefound in the coordination, mechanism oneof the vacant coordination site is formed. This free site for coordination lacks in the classical cyclometalation reaction: in the step from chelate to monodentate coordination, one cyclometalation reaction; • vacantthe final coordination rollover product site is formed. has a free This heteroatom free site for (N co inordination the majority lacks of cases) in the able classical to cyclometalationundergo successive reaction; reactions or interactions: coordination, protonation, hydrogen- • thebond final interactions, rollover product return has to initiala free chelation,heteroatom etc. (N Here in the lies majority the crucial of cases) difference able to undergobetween successive rollover and reactions classical or cyclometalated interactions: complexes:coordination, three protonation, consequences hydrogen- of this bondaspect interactions, are: return to initial chelation, etc. Here lies the crucial difference between- the rollover retro-rollover and classical process, cyclometalated i.e., the reverse reactioncomplexes: of rollover three cyclometalationconsequences of (see this aspectSection are: 4.1.5): In these steps, one hydrogen is lost and regained, with interesting applications in catalytic hydrogen transfer reactions (see Section 6.2). - - theThe retro-rollover double rollover process, cyclometalation, i.e., the revers whiche reaction allows for of therollover synthesis cyclometalation of planar, (seehighly Section delocalized 4.1.5): In bi- these or polynuclear steps, one complexes hydrogen (see is lost Section and 4.1.3regained,). with inter- - estingThe protonation applications of in the catalytic free donor hydrog usuallyen transfer allows thereactions formation (see ofSection uncommon 6.2). NHC (nitrogen heterocyclic carbenes), formally neutral ligands, which are isomers - Theof the double neutral rollover starting cyclometalation, ligand. This option which enters allows rollover for complexes the synthesis into the of family planar, highlyof “ligands delocalized with multiple bi- or polynuclear personalities” complexes [8] rather (see than Section being 4.1.3). mere spectator ligands (see Section 4.1.5). • - Finally,The protonation it should be of noted the thatfree “rollover”donor usua ligandslly allows are the deprotonated formation formsof uncommon of the startingNHC neutral (nitrogen ligands, heterocyclic whose chelated carbenes), complexes formally are neutral usually ligands, stable andwhich difficult are iso- to activate.mers of Thethe strengthneutral starting of the M–E ligand. and M–CThis bonds,option as enters well asrollover mechanisms complexes of C–H into bondthe activation family of vary “ligands from metal with to multiple metal, so personalities” that each metal [8] will rather have athan different being story. mere Thisspectator accounts ligands for the difficulties(see Section to 4.1.5). find general rules for rollover cyclometalation. For all these reasons, rollover cyclometalation constitute a potent instrument for the • regioselectiveFinally, it should C–H bond be noted activation that and“rollover” functionalization ligands are of deprotonated the C–H bond forms located of inthe posi- start- tionsing usually neutral not ligands, available whose for metal-mediated chelated complexes C–H activation, are usually as wellstable as and for the difficult synthesis to ac- of compoundstivate. The strength with novel of the properties. M–E and This M–C review bonds, will as bewell focused as mechanisms on the application of C–H bond of rollover metalation to regioselective C–H bond activation and functionalization processes. Both stochiometric and catalytic activation/functionalization will be treated. However,

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activation vary from metal to metal, so that each metal will have a different story. activationThis accounts vary for from the metaldifficulties to metal, to find so generalthat each rules metal for willrollover have cyclometalation. a different story. ThisFor all accounts these reasons, for the difficultiesrollover cyclometalat to find generalion constitute rules for rollovera potent cyclometalation. instrument for the regioselectiveFor all these C–H reasons, bond activation rollover cyclometalat and functionalizationion constitute of the a potent C–H bond instrument located for in thepo- regioselectivesitions usually C–H not availablebond activation for metal-mediated and functionalization C–H activation, of the C–Has well bond as forlocated the synthe- in po- sitionssis of compounds usually not with available novel for properties. metal-mediated This re viewC–H willactivation, be focused as well on asthe for application the synthe- of sisrollover of compounds metalation with to regioselective novel properties. C–H This bond re activationview will beand focused functionalization on the application processes. of Molecules 2021, 26, 328 rolloverBoth stochiometric metalation toand regioselective catalytic activation/fun C–H bond activationctionalization and willfunctionalization be treated.4 However, of processes. 58 in Bothorder stochiometric to furnish a more and catalyticample vision activation/fun of the reacctionalizationtion, we will alsowill reportbe treated. examples However, of reac- in ordertivity toand furnish applications a more ofample rollover vision cyclometalated of the reaction, complexes. we will also report examples of reac- tivityin order and to applications furnish a more of ample rollover vision cyclometalated of the reaction, complexes. we will also report examples of reactivity2. History and of applicationsRollover Cyclometalation of rollover cyclometalated complexes. 2. HistoryTo the of best Rollover of our Cyclometalationknowledge, the first rollover complex appeared in the literature in 2. History of Rollover Cyclometalation 1975,To only the besttwo ofyears our knowledge,after Trofimenko’s the first rolloverrecognition complex of the appeared cyclometalation in the literature reaction: in To the best of our knowledge, the ﬁrst rollover complex appeared in the literature Giordano and Rasmussen simply described the Pt(II) and Pd(II) rollover-cyclometalated 1975,in 1975, only only two two years years afterafter Troﬁmenko’s Trofimenko’s recognition recognition of the of cyclometalation the cyclometalation reaction: reaction: Giordanoproducts and ofand 2-(2’-thienyl)pyridine, Rasmussen Rasmussen simply simply described described 1 (Figure the Pt(II)3),the as Pt(II) and“Compounds Pd(II) and Pd(II) rollover-cyclometalated Containing rollover-cyclometalated Metal-Carbon productsBonds” [9] of of 2-(2 without2-(2’-thienyl)pyridine,0-thienyl)pyridine, recognizing1 their(Figure 1 (Figure novelty.3), as 3), “Compounds as “Compounds Containing Containing Metal-Carbon Metal-Carbon Bonds” [9[9]] without without recognizing recognizing their their novelty. novelty.

Figure 3. The first rollover complexes. Figure 3.3.The The ﬁrst first rollover rollove complexes.r complexes. Soon later, in 1977, Watts and coworkers reported the synthesis of an Ir(III) species, Soon later, in 1977, Watts and coworkers reported the synthesis of an Ir(III) species, initiallySoon described later, in 1977,as an Watts iridium(III) and coworkers complex reportedcontaining the a synthesismonodent 0ofate an 2,2’-bipyridine, Ir(III) species, initially described as an iridium(III) complex containing a3+ monodentate 2,2 -bipyridine, initiallyrelated todescribed the well-known as an iridium(III) cationic complex comple [Ir(bpy)x containing3+ 3] (complex a monodent 2) [10].ate Only 2,2’-bipyridine, after a long related to the well-known cationic complex [Ir(bpy)3] (complex 2)[10]. Only after a long relatedandand controversialcontroversial to the well-known debate, debate, several cationicseveral years yearscomplex later, later, the [Ir(bpy) nature the nature of3]3+ the (complex of complex the complex 2 was) [10]. determined Only was determinedafter a long andbyby meansmeans controversial of of X-ray X-ray and debate, and NMR NMR several studies studies [11years– [11–15]15] later, as having as the having twonature N, two Nof chelated N,the N complex chelated bipyridines was bipyridines anddetermined and byoneone means N,N, C C cyclometalated cyclometalatedof X-ray and bipy,NMR bipy, the studies the latter latter being[11–15] being a neutralas ahaving neutral ligand, two ligand, due N, toN due protonationchelated to protonation bipyridines of the of and the oneuncoordinateduncoordinated N, C cyclometalated nitrogen nitrogen (Figure (Figurebipy,4, complexthe 4, lattercomplex3 ).being 3). a neutral ligand, due to protonation of the uncoordinated nitrogen (Figure 4, complex 3).

FigureFigure 4. 4.The The first first iridium iridium rollover rollover complex. complex. Figure 4. The first iridium rollover complex. TheThe term term roll-over roll-over was was coined coined by Skapski, by Skapski, Sutcliffe, Sutcliffe, and Young and in Young 1985 [16 in], 1985 describing [16], describ- the thermal rearrangement of (Ar)2(bpy)platinum(II) complexes: no mononuclear species ing the thermal rearrangement of (Ar)2(bpy)platinum(II) complexes: no mononuclear spe- wereThe isolated term but roll-over the metalation was coined was by confirmed Skapski, by Sutcliffe, the X-ray and structure Young of in a 1985 dinuclear [16], describ- ingspecies.cies the were thermal Interestingly, isolated rearrangement but the the reaction metalation of finally (Ar) was2 leads(bpy)platinum(II) co tonfirmed the isolation by thecomplexes: of X-ray the largely structure no delocalized mononuclear of a dinuclear spe- species. Interestingly, the reaction finally leads to the isolation of the largely delocalized ciesorganometallic were isolated polymer but the [Pt(bipy-2 metalationH)]n, was4, having confirmed bridging by double-rolloverthe X-ray structure bipyridines of a dinuclear (Figurespecies.organometallic5). Interestingly, Kinetic polymer measurements the [Pt(bipy-2reaction showed finallyH)] thatn, 4 theleads, having rollover to the bridging reaction isolation isdoub fasterof thele-rollover starting largely from delocalizedbipyridines organometallic[Pt(bipy)(4-t-but-Ph) polymer2] in comparison [Pt(bipy-2 toH [Pt(bipy)(4-CF)]n, 4, having3 -Ph)bridging2]. double-rollover bipyridines Since then, the term roll-over was not used until 1999, when Minghetti’s group reported a series of Pt(II) and Pd(II) rollover complexes with substituted 2,20-bipyridines (see later) [17].

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Molecules 2021, 26, 328 5 of 58 (Figure 5). Kinetic measurements showed that the rollover reaction is faster starting from [Pt(bipy)(4-t-but-Ph)2] in comparison to [Pt(bipy)(4-CF3-Ph)2].

Figure 5.5.Thermal Thermal rearrangement rearrangement of [Pt(bipy)(Ar)of [Pt(bipy)(Ar)2] affording2] affording the organometallic the organometallic polymer polymer 4. Adapted 4. withAdapted permission with permission from J. Chem. from Soc. J. Chem. Chem. Soc. Commun Chem. .Commun1985, 609–611.. 1985, 609–611. Copyright Copyright (1985) Royal (1985) Society Royal ofSociety Chemistry. of Chemistry.

FromSince then,then, anthe increasingly term roll-over number was not of papers used until have 1999, appeared when in Minghetti’s the literature, group demon- re- strating,ported a inter-alia,series of Pt(II) by the and publication Pd(II) rollover of two complexes reviews completelywith substituted dedicated 2,2’-bipyridines to the subject(see [later)7,18] [17]. with other reviews also dealing in part with the same theme [19]. Potential applicationsFrom then, in organican increasingly synthesis, number homogeneous of papers have catalysis, appeared biomedicine, in the literature, and advanced demon- materialsstrating, inter-alia, are revealing by the the publication hidden potentialities of two reviews in this completely field. dedicated to the subject [7,18] with other reviews also dealing in part with the same theme [19]. Potential applica- 3. Mechanism of Rollover Cyclometalation tions in organic synthesis, homogeneous catalysis, biomedicine, and advanced materials are revealingThe activation the hidden of C–H potentialities bonds in homogeneous in this field. systems has been a matter of study for many years. From a mechanistic point of view, it is generally accepted that, in cyclometala- tion3. Mechanism reactions, C–Hof Rollover bond activation Cyclometalation follows three major pathways: electrophilic activation (or heterolytic cleavage), oxidative addition, and σ-bond metathesis [1,2,20]. The activation of C–H bonds in homogeneous systems has been a matter of study for The operating mechanism depends on several factors, such as the electronic nature many years. From a mechanistic point of view, it is generally accepted that, in cyclomet- of the L M fragment and the nature of the C–H bond, and in most cases, it is far from alation reactions,n C–H bond activation follows three major pathways: electrophilic activa- being determined. The comprehension of the mechanism is complicated by the fact that tion (or heterolytic cleavage), oxidative addition, and σ-bond metathesis [1,2,20]. subtle structural modifications in the ligand or in the metal center may deeply influence The operating mechanism depends on several factors, such as the electronic nature the reaction pathway. of the LnM fragment and the nature of the C–H bond, and in most cases, it is far from C–H bond activation via electrophilic activation is common for electron-poor late being determined. The comprehension of the mechanism is complicated by the fact that transition metals such as palladium(II), and, to some extent, also platinum(II). This pathway subtle structural modifications in the ligand or in the metal center may deeply influence is operative especially in the case of C(sp2)–H activations in aromatic rings. Mechanistic the reaction pathway. studies on aromatic C–H bond activation revealed that electron-donating substituents on theC–H ring bond favors activation the metal-mediated via electrophilic activation, activation in analogyis common to electrophilicfor electron-poor aromatic late substitutionstransition metals in organic such as compounds. palladium(II), and, to some extent, also platinum(II). This path- 2 way Inis operative contrast, oxidative especially addition in the case pathways of C(sp require)–H activations electron-rich in low-valent aromatic rings. metal Mecha- centers andnistic is studies common on foraromatic late transition C–H bond metals, activati suchon revealed as Ru, Os, that Rh, electron-donating Ir, Pt; also, it seems substitu- to be preferredents on the in ring C(alkyl)–H favors the bond metal-mediated activations. activation, in analogy to electrophilic aromatic substitutionsThe σ-bond in organic metathesis compounds. pathway has been considered a prevalent mechanism in the case ofIn electron-poorcontrast, oxidative metal addition centers such pathways as high-valent require electron-rich early transition low-valent metals. Inmetal the casecen- ofters late and transition is common metals, for suchlate transition as Pt(II) and metals, Pd(II), such the metalas Ru, supports Os, Rh, Ir, the Pt; stabilization also, it seems of the to σbecomplex preferred and in theC(alkyl)–H process hasbond been activations. designated σ-CAM, σ-complex assisted metathesis. ItThe is worthσ-bond to metathesis note that anpathway oxidative has addition been cons pathwayidered a produces prevalent a mechanism hydride complex; in the however,case of electron-poor subsequent metal reductive centers eliminations such as hi ofgh-valent HX (X = early coordinated transition anionic metals. ligand) In the maycase affordof late finaltransition cyclometalation metals, such products as Pt(II) without and Pd(II), the expected the metal coordinated supports the hydride, stabilization making of it difficultthe σ complex to distinguish and the itprocess from the has other been twodesignated mechanisms. σ-CAM, σ-complex assisted metathesis. A final, particular case regards trasmetalation reactions (in this case, transcyclometala- tion)It which is worth do not to note involve that a directan oxidative C–H bond addition activation pathway but require produces a starting a hydride organometal- complex; lichowever, compound subsequent for the exchangereductive reactioneliminations M-C +of M’-X HX (X→ =M-X coordinated + M’-C. anionic ligand) may affordIn final rollover cyclometalation cyclometalation, products some withou aspectst the of theexpected process coordinated are different hydride, from classical making cyclometalation.it difficult to distinguish Most the it from experimental the other andtwo DFTmechanisms. studies on the operating mechanism regarded platinum(II) bipyridine complexes. Changing metal and bidentate ligand may obviously result in a different mechanism. Starting from the usual NˆN adduct, detachment of the nitrogen and internal rotation are the crucial differences between classical and rollover cyclometalation; in the latter, a coordination position is liberated by the nitrogen,

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A final, particular case regards trasmetalation reactions (in this case, transcyclomet- alation) which do not involve a direct C–H bond activation but require a starting organometallic compound for the exchange reaction M-C + M’-X → M-X + M’-C. In rollover cyclometalation, some aspects of the process are different from classical cyclometalation. Most the experimental and DFT studies on the operating mechanism regarded platinum(II) bipyridine complexes. Changing metal and bidentate ligand may ob- Molecules 2021 26 , , 328 viously result in a different mechanism. Starting from the usual N^N adduct, detachment6 of 58 of the nitrogen and internal rotation are the crucial differences between classical and rollover cyclometalation; in the latter, a coordination position is liberated by the nitrogen, differentlydifferently fromfrom thethe classicalclassical case.case. TheseThese twotwo stepssteps allowallow interactioninteraction ofof thethe C(3)-HC(3)-H bondbond withwith thethe metalmetal center.center. AsAs forfor rolloverrollover cyclometalation, cyclometalation, the the operative operative mechanisms mechanisms of theof the C–H C–H bond bond activation activa- steption arestep expected are expected to be to the be same the same as in as classical in classical cyclometalation. cyclometalation. All three All three mechanisms mechanisms have beenhave postulatedbeen postulated to be effectiveto be effectiv withe differentwith different metals metals and ligands. and ligands. InIn thethe case case of electron-rich of electron-rich Pt(II) complexes, Pt(II) complexes, such as [PtMe such2(DMSO) as [PtMe2] or [PtMe2(DMSO)2(SMe2]2 )]or2, an[PtMe oxidative2(SMe2)] addition2, an oxidative pathway addition has been pathway proposed has been by several proposed authors. by several Schwarz authors. and coworkersSchwarz and conducted coworkers a mechanistic conducted study, a mechanistic based on CID-MSstudy, based (collision on CID-MS induced (collision dissociation in- massduced spectrometry) dissociation mass and DFTspectrometry) calculations, and on DF theT calculations, gas-phase rollover on the gas-phase transformation rollover of + + [M(bipy)X]transformationto of [M(bipy- [M(bipy)X]H)] + tospecies [M(bipy- (MH =)] Ni,+ species Pd, Pt; (M X = Ni, = CH Pd,3, Pt; Cl), X = founding CH3, Cl), afound- clear preferenceing a clear forpreference the oxidative-addition/reductive-elimination for the oxidative-addition/reductive-elimination pathway for pathway Pt (Figure for6 ),Pt whereas(Figure 6), in thewhereas case of in Ni(II), the case an s-bondof Ni(II), metathesis an s-bond is metathesis preferred. Foris pref palladium,erred. For the palladium, preferred mechanismthe preferred depends mechanism on the depends nature ofon thethe anionicnature of ligands the anionic X: s-bond ligands metathesis X: s-bond is favoredmetath- foresis [Pd(bipy)Me] is favored for+, whereas[Pd(bipy)Me] oxidative+, whereas addition/reductive oxidative addition/reductive elimination is slightly elimination preferred is + inslightly the case preferred of [Pd(bipy)(Cl)] in the case [of21 [Pd(bipy)(Cl)]]. + [21].

FigureFigure 6.6. Proposed mechanismmechanism forfor thethe gas-phasegas-phase rolloverrollover cyclometalationcyclometalation ofof [Pt(bipy)X]+.[Pt(bipy)X]+.

TheThe studiesstudies inin thethe solutionsolution essentiallyessentially regarded regarded [PtMe [PtMe2(DMSO)2(DMSO)2]2] and and [PtPh [PtPh22(DMSO)(DMSO)22]] derivatives.derivatives. Young andand coworkers,coworkers, inin theirtheir pivotalpivotal workwork inin 19851985 [[16],16], foundfound thatthat electronelectron richerricher Pt(II) derivatives derivatives [PtAr [PtAr2(DMSO)2(DMSO)2]2 reacted] reacted faster faster than than electron electron poorer poorer analogues analogues (Ar t (Ar= 4-t =Bu-C 4- Bu-C6H4; 64-CFH4; 4-CF3-C6H3-C4). 6H4). 0 Minghetti,Minghetti, Zucca, and co-workers co-workers working working with with 2,2’-bipyridine 2,2 -bipyridine and and several several 5- 5-and and 6- 0 6-substitutedsubstituted 2,2’-bipyridines 2,2 -bipyridines found found via via NMR NMR spectroscopy spectroscopy that that the theprocess process follows follows a con- a consecutivesecutive reaction reaction mechanism, mechanism, which which begins begins with with initial initial N^N NˆN chelation to produceproduce [Pt(NˆN)(CH[Pt(N^N)(CH33))22],], followedfollowed byby rapidrapid methanemethane liberationliberation [[17,22].17,22]. ForFor thethe ﬁnalfinal steps,steps, i.e.,i.e., thethe crucialcrucial C–HC–H bondbond activationactivation andand successivesuccessive eliminationelimination of of methane, methane, the the proposed proposed mecha- mech- nismanism involves, involves, also also in thein solution,the solution, an oxidative-addition/reductive-elimination an oxidative-addition/reductive-elimination sequence se- whichquence eventually which eventually liberates methane.liberates methane. No sign of No hydride sign of intermediates hydride intermediates was observed was in theob- solutionserved in in the the solution case of platinum,in the case however, of platinum, Zuber however, and Pruchnik Zuber studied and Pruchnik the behavior studied in thethe solution of the [Rh(bipy) Cl] complex reporting the NMR detection of rhodium-hydride in- behavior in the solution 2of the [Rh(bipy)2Cl] complex reporting the NMR detection of rho- termediates in a reversible rollover/retro-rollover process (see Section 4.1.7). Analogously, dium-hydride intermediates in a reversible rollover/retro-rollover0 process (see section the reaction of a Rh(I) NHC complex, [Rh(NHC)(C2H4)(Cl]2 with 2,2 -biquinoline gave, at 4.1.7). Analogously, the reaction of a Rh(I) NHC complex, [Rh(NHC)(C2H4)(Cl]2 with 2,2’- room temperature, the rollover hydride [Rh(NHC)(Cl)(H)(NˆC)], where NˆC is a rollover biquinoline gave, at room temperature, the rollover hydride [Rh(NHC)(Cl)(H)(N^C)], coordinated 2,20-biquinoline [23]. where N^C is a rollover coordinated 2,2’-biquinoline [23]. The experimental data indicate that, in the case of the [Pt(NˆN)Me2] intermediate, The experimental data indicate that, in the case of the [Pt(N^N)Me2] intermediate, de-coordination of nitrogen is favored by the high trans-inﬂuence of the methyl ligand, de-coordination of nitrogen is favored by the high trans-influence of the methyl ligand, a a bulky and/or electron attracting substituent in position 6 (which increases the steric bulky and/or electron attracting substituent in position 6 (which increases the steric con- congestion in the square-planar and/or reduces the donor ability of the nitrogen). In particular, the CF3 substituent favors the reaction also in 5-position, furnishing a clear electronic effect on the outcome of the reaction. Oxidative-addition mechanism was also proposed by Wang and coworkers in the rollover activation of another “PtMe2” adduct [Pt(NˆN)Me2] (See Section 4.2.1, complex 76) [24]. The authors assumed an oxidative-addition reductive-elimination pathway for the process, based on the electron-richness of the Pt center in the three-coordinate intermediate and on the formation of only one isomer as a result of the process. An oxidative-addition pathway was also proposed for the Rh-catalyzed selective functionalization of 2-(2-thienyl)pyridine (see Section 6.2.1)[25]. Molecules 2021, 26, 328 7 of 58

At variance, Thiel and coworkers, in their review on the argument [18], proposed that the final step of the roll-over cyclometalation of aromatic nitrogen donors is analogous to a classical organic SEAr reaction, where the metal acts as the electrophile. Therefore, “the more electron-rich the ring system is, the more reactive it should be.“ This is not in line 0 with the extreme rapidity of the reaction of 6-CF3-2,2 -bipyridine with [PtMe2(DMSO)2] 0 (and even 5-CF3-2,2 -bipyridine) but it should be suitable on the basis that different metals (and also different metal precursors of the same metal) may act following different reaction mechanisms. In agreement with an electrophilic mechanism is the rollover cyclometalation of 2,20:60,2”-terpyridine promoted by Pt(II), where a two-fold C–H bond activation occurs on the central pyridine ring. After the first cyclometalation, the central pyridine (with a higher electron density due to metalation) is activated towards a second metalation, which occurs faster than the first one [26]. Accordingly, reaction of [Ir(Cp*)Cl2]2 with 2-(2-dimethylaminopyrimidin-4-yl)pyridine gave the rollover cationic complex [Ir(Cp*)NˆC)Cl]+, a behavior in agreement with an electrophilic aromatic substitution [27]. On the other hand, a σ-bond metathesis pathway is suggested by a DFT analysis of the room-temperature rollover cyclometalation of palladium(II) complexes with phosphine pyrazole pincer ligands PˆCˆN (PCN = 1-[3-[(di-tert-butylphosphino) methyl]phenyl]-1H- pyrazole) and = 1-[3-[(di-tert-butylphosphino)methyl]phenyl]-5-methyl-1H-pyrazole, see Section 4.2.1)[28]. DFT data revealed low energy barriers for C–H activation through a σ-bond metathesis reaction, in line with the experimental outcomes. Finally, quite recently, a C–H bond rollover activation which precedes nitrogen coordination was proposed for the reactions of 2,20-bipyridines with a hexahydride bipyridine osmium complex (see Section 4.1.7, Osmium). The C–H bond activation step consists in a hydride-mediated heterolytic cleavage of the C–H bond, promoted by the electrophilic Os(IV) complex formed by H2 reductive elimination. C–H bond selectivity is the consequence of nitrogen trapping of the intermediate formed by C–H activation. Comparable considerations are likely true for the corresponding reaction of a pentahydride iridium complex [29].

4. C–H Bond Activation Through Rollover Cyclometalation During the last years, several metals showed the ability to promote rollover cyclometalation with an ample series of substrates. A variety of rollover cyclometalated complexes have been synthesized and studied. In this chapter, we will examine stoichiometric cyclometalation reactions, dividing the discussion according to typologies of ligands and metal involved.

4.1. Bipyridine Complexes In 2020, 2,20-bipyridine (bpy) celebrated 132 years from its discovery, which occurred in 1888. Bipyridine is undoubtedly one of most important ligands in coordination chemistry, so that some years ago, a review recognized it as “the most widely used ligand” [30]. It is well-known that the common coordinative behavior of 2,20-bipyirine is as a chelated NˆN ligand, even though monodentate and bridging complexation is recognized, although rare. For these reasons, the new examples of metalating behavior aroused interest, and researchers struggled to ﬁnd methods to induce this ligand to leave the comfortable NˆN behavior for the “new way”. Although several ligands can behave in a rollover mode, as seen before, 2,20-bipyridine remains the prototypical and most important ligand in this ﬁeld. It is also worth to note that an NˆC-rollover coordinated bipyridine is not precisely (not only, at least) a bipyridine coordinated in a new way, but is a formally anionic C(3)-deprotonated 2,20-bipyridyl.

4.1.1. Platinum and Palladium Complexes After Young’s pivotal paper, the term “rollover”, along with the concept itself of “rollover cyclometalation” was not recognized for several years, until in 1999 Minghetti’s Molecules 2021, 26, x FOR PEER REVIEW 8 of 59

For these reasons, the new examples of metalating behavior aroused interest, and researchers struggled to find methods to induce this ligand to leave the comfortable N^N Molecules 2021, 26, x FOR PEER REVIEWbehavior for the “new way”. Although several ligands can behave in a rollover 8mode, of 59 as

seen before, 2,2’-bipyridine remains the prototypical and most important ligand in this field. It is also worth to note that an N^C-rollover coordinated bipyridine is not precisely (not only,For atthese least) reasons, a bipyridine the new coordinated examples of in me atalating new way, behavior but is aroused a formally interest, anionic and C(3)- deprotonatedresearchers struggled 2,2’-bipyridyl. to find methods to induce this ligand to leave the comfortable N^N behavior for the “new way”. Although several ligands can behave in a rollover mode, as 4.1.1.seen Platinum before, 2,2’-bipyridine and Palladium remains Complexes the prot otypical and most important ligand in this field. It is also worth to note that an N^C-rollover coordinated bipyridine is not precisely After Young’s pivotal paper, the term “rollover”, along with the concept itself of (not only, at least) a bipyridine coordinated in a new way, but is a formally anionic C(3)- “rolloverdeprotonated cyclometalation” 2,2’-bipyridyl. was not recognized for several years, until in 1999 Minghetti’s group in Sassari re-submitted the term, reporting the rollover cyclometalation of 6-substituted-2,2’-bipyridines4.1.1. Platinum and Palladium (6-R-2,2’-bipyiridines, Complexes R = isopropyl, neopentyl, and tert-butyl) by Molecules 2021, 26, 328 means ofAfter Pt(II) Young’s and Pd(II) pivotal precursors paper, the [17]. term “rollover”, along with the concept8 ofitself 58 of “rolloverThe paper cyclometalation” reported the was first not case recognized of bipyri fordine several rollover years, cyclometalation until in 1999 Minghetti’s promoted by palladium:group in Sassaristarting re-submitted from Pd(II) the acetate, term, report a well-knowning the rollover cyclometalating cyclometalation precursor, of 6-substi- mono andtuted-2,2’-bipyridines dinucleargroup in Sassari complexes re-submitted (6-R-2,2’-bipyiridines, were the isolated term, reporting and Rcharacterizedthe = isopropyl, rollover cyclometalation neopentyl,(5 and 6, R and of = 6-substituted- isopropyl tert-butyl) andby ne- 0 0 opentyl,means2,2 -bipyridines Figureof Pt(II) 7). and The (6-R-2,2 Pd(II) substituent-bipyiridines, precursors in [17]. Rposition = isopropyl, 6 resulted neopentyl, in andbeingtert -butyl)crucial by for means the reaction, likelyof forThe Pt(II) papersteric and Pd(II) reportedreasons. precursors the In first [17the case]. same of bipyri paper,dine rolloverfollowing cyclometalation Young’s discovery, promoted bytrans - palladium:The paperstarting reported from thePd(II) ﬁrst acetate, case of bipyridine a well-known rollover cyclometalating cyclometalation promotedprecursor, by mono [PtClMe(SMe2)2] was reacted with 6-tert-butyl-2,2’-bipyridine affording the rollover com- andpalladium: dinuclear starting complexes from Pd(II)were acetate,isolated a well-knownand characterized cyclometalating (5 and 6 precursor,, R = isopropyl mono and and ne- plex 7dinuclear. In addition, complexes in werethis isolatedcase, under and characterized the reaction (5 and conditions6, R = isopropyl studied, and neopentyl, the bulky alkyl opentyl, Figure 7). The substituent in position 6 resulted in being crucial for the reaction, substituentFigure7 in). Theposition substituent 6 resulted in position in bein 6 resultedg crucial in being for crucial the outcome for the reaction, of the likelyreaction. for likely for steric reasons. In the same paper, following Young’s discovery, trans- steric reasons. In the same paper, following Young’s discovery, trans-[PtClMe(SMe2)2] was [PtClMe(SMereacted with2)2 6-] tert-wasbutyl-2,2 reacted0 -bipyridinewith 6-tert- affordingbutyl-2,2’-bipyridine the rollover complex affording7. In the addition, rollover in com- plexthis 7. case,In addition, under the in reaction this case, conditions under studied,the reaction the bulky conditions alkyl substituent studied, in the position bulky 6 alkyl substituentresulted in in being position crucial 6 resulted for the outcome in bein ofg crucial the reaction. for the outcome of the reaction.

Figure 7. Rollover and tridentate N^N^C complexes with 6-substituted 2,2’-bipyridines.

It is worth to note that under different reaction conditions,0 e.g., from [MCl4]2− precur- FigureFigure 7. Rollover 7. Rollover and tridentate and tridentate NˆNˆC complexes N^N^C withcomplexes 6-substituted with 6-substituted 2,2 -bipyridines. 2,2’-bipyridines. sors in water/HCl (M = Pd, Pt), the reaction proceeded in a different way, activating a C– 2− It is worth to note that under different reaction conditions, e.g., from [MCl4] precur- H bondIt in is theworth substituent to note that to under give thediffer correntesponding reaction conditions, [M(N^N^C)Cl] e.g., from tridentate [MCl4]2− precur- complexes sors in water/HCl (M = Pd, Pt), the reaction proceeded in a different way, activating a C–H 8 andsorsbond 9 in (M water/HCl in =the Pd, substituent Pt) (M [31–35]. = Pd, to givePt), The the the topic correspondingreaction of C–H proceeded re [M(NˆNˆC)Cl]gioselectivity in a different tridentate in suway,bstituted complexes activating bipyridines8 a C– andH related bondand 9 in(M ligands the = Pd, substituent Pt) is [31 complex,–35]. to The give topicbeing the of corr the C–Hesponding reaction regioselectivity outcome [M(N^N^C)Cl] in substituted driven tridentate by bipyridines several complexes and factors, and will8 andberelated treated 9 (M ligands = Pd,later. isPt) complex, [31–35]. being The thetopic reaction of C–H outcome regioselectivity driven by severalin substituted factors, and bipyridines will andAfterbe related treated a series ligands later. of isstudies complex, dedicated being the to reaction related outcome polycyclic driven bipyridine by several systems, factors, and such as will be treatedAfter a serieslater. of studies dedicated to related polycyclic bipyridine systems, such as 2,2’:6’,2’’-terpyridine0 0 and 6,6’-Ph0 2-bipyridine (see later), the investigation was extended to 2,2 :6 ,2”-terpyridine and 6,6 -Ph2-bipyridine (see later), the investigation was extended to After a series of studies dedicated toR related polycyclic bipyridine systems, such as a seriesa series of 6-substi of 6-substituedtued bipyridines bipyridines (bpy(bpyR, Figure, Figure8)[ 228)][22] and comparedand compared to unsubstituted to unsubstituted 2,2’:6’,2’’-terpyridine and 6,6’-Ph2-bipyridine (see later), the investigation was extended to 2,2’-bipyridine2,20-bipyridine [36], [36 evincing], evincing the the role of of the the substituent substituent in the in reaction. the reaction. a series of 6-substitued bipyridines (bpyR, Figure 8) [22] and compared to unsubstituted 2,2’-bipyridine [36], evincing the role of the substituent in the reaction.

FigureFigure 8. 6-substituted-2,2’-bipyridines. 8. 6-substituted-2,20-bipyridines. C(3) C(3) and and C(3C(3’)0) positions, positions, involved involved in rollover in rollover activation, activation, are shown.Figureare shown.8. 6-substituted-2,2’-bipyridines. C(3) and C(3’) positions, involved in rollover activation, are shown. In the Sassari Laboratory of Organometallic Chemistry, the study involved the reaction a series of Pt(II) precursors such as [PtMe2(DMSO)2], [PtPh2(DMSO)2], [PtMeCl(DMSO)2], [PtCl2(DMSO)2] with several substituted bipyridines. The most electron-rich complex, i.e., [PtMe2(DMSO)2], showed to be the best Pt(II) precursor for the synthesis of bipyridine rollover complexes 10 (Figure9). A clear steric inﬂuence of the substituent was evidenced 0 by the fast reaction of [PtMe2(DMSO)2] with 6-tert-butyl-2,2, -bipyridine, with C(3)–H bond rollover activation even at room temperature. In comparison, 2,20-bipyridines with less steric-demanding substituents such as Me or neo-pentyl, needed higher temperatures (acetone, 40–60 ◦C). In the absence of a substituent, i.e., with 2,20-bipyridine, the activation occurs only under hasher conditions, such as reﬂuxing toluene [36]. A kinetic study showed Molecules 2021, 26, x FOR PEER REVIEW 9 of 59

Molecules 2021, 26, x FOR PEER REVIEW 9 of 59

In the Sassari Laboratory of Organometallic Chemistry, the study involved the reaction a series of Pt(II) precursors such as [PtMe2(DMSO)2], [PtPh2(DMSO)2], In the Sassari Laboratory of Organometallic Chemistry, the study involved the reac- [PtMeCl(DMSO)2], [PtCl2(DMSO)2] with several substituted bipyridines. The most elec- tion a series of Pt(II) precursors such as [PtMe2(DMSO)2], [PtPh2(DMSO)2], tron-rich complex, i.e., [PtMe2(DMSO)2], showed to be the best Pt(II) precursor for the syn- [PtMeCl(DMSO)2], [PtCl2(DMSO)2] with several substituted bipyridines. The most elec- thesistron-rich of complex,bipyridine i.e., rollover [PtMe2(DMSO) complexes2], showed 10 (Figure to be the 9). best A Pt(II)clear precursorsteric influence for the syn- of the sub- stituentthesis of wasbipyridine evidenced rollover by complexes the fast reaction 10 (Figure of 9).[PtMe A clear2(DMSO) steric influence2] with 6- oftert the-butyl-2,2,’-bi- sub- pyridine,stituent was with evidenced C(3)–H by bond the rolloverfast reaction activation of [PtMe even2(DMSO) at room2] with temperature. 6-tert-butyl-2,2,’-bi- In comparison, Molecules 2021, 26, 328 2,2’-bipyridinespyridine, with C(3)–H with bond less steric-demanding rollover activation even substituents at room temperature. such as Me orIn comparison,neo-pentyl,9 of 58 needed higher2,2’-bipyridines temperatures with less (acetone, steric-demanding 40–60 °C). su bstituentsIn the absence such as ofMe a or substituent, neo-pentyl, neededi.e., with 2,2’- bipyridine,higher temperatures the activation (acetone, occurs 40–60 only °C). underIn the absencehasher conditions,of a substituent, such i.e., as refluxingwith 2,2’- toluene bipyridine, the activation occurs only under hasher conditions, such as refluxing toluene [36].that the A rolloverkinetic processstudy entailsshowed a consecutive that the rollo reactionver throughprocess the entails detectable a consecutive intermediate reaction [36]. AR kinetic study showed that the rolloverR process entails a consecutive reaction throughPt(bpy )Me the2. detectable intermediate Pt(bpy )Me2. through the detectable intermediate Pt(bpyR)Me2.

Figure 9. Rollover cyclometalation of 6-substituted 2,2’-bipyridines0 with [PtMe2(DMSO)2]. Adapted Figure 9.9.Rollover Rollover cyclometalation cyclometalation of 6-substituted of 6-substituted 2,2 -bipyridines 2,2’-bipyridines with [PtMe with2(DMSO) [PtMe22(DMSO)]. Adapted2]. Adapted with permission from Organometallics 2003, 22, 23, 4770–4777. Copyright (2003) American Chemical with permissionpermission from fromOrganometallics Organometallics2003 2003, 22,, 23,22, 4770–4777.23, 4770–4777. Copyright Copyright (2003) (2003) American American Chemi- Chemical Society. Society.cal Society. According to the Pt/bipyPt/bipy molar molar ratio, ratio, the the reaction afforded the mononuclear com- According to the Pt/bipy molar ratio, the reaction afforded the mononuclear compound (1:1 Pt:bipy molar ratio)ratio) oror thethe dinucleardinuclear “double“double rollover”rollover” complexcomplex (2:1(2:1 Pt:bipyPt:bipy poundmolar ratio) (1:1 Pt:bipy by meansmeans molar ofof doubledouble ratio) C(3)-HC(3)-H or the andand dinuclear C(3C(3’)-H0)-H “double bondbond activation.activation. rollover” In complex thethe dinucleardinuclear (2:1 Pt:bipy molarcomplex, ratio) a a twofold twofold by means deprotonated deprotonated of double 2,2’-bipyridine 2,2 C(3)-H0-bipyridine and acts C(3’)-H acts as asa planar, a bond planar, formally activation. formally dianionic, dianionic,In the de- dinuclear complex,delocalizedlocalized ligand, a ligand,twofold connecting connecting deprotonated two two me metaltal 2,2’-bipyridine centers centers (see (see Section Section acts 4.1.4).as 4.1.4 a planar, ). formally dianionic, de- localizedThe succeeding ligand, connecting studies were two extended metal centers to twotwo ligands(see Section with 6-membered 4.1.4). fused rings: the chiralThechiral pinene-derivedsucceeding pinene-derived studies ligand ligand were (5S,7S)-5,7-methane-6,6-dimethyl-2-(pyridin-2-yl)-5,6,7,8- extended(5S,7S)-5,7-methane-6,6-dimethyl-2-(pyridin-2-yl)- to two ligands with 6-membered fused rings: tetrahydroquinoline5,6,7,8-tetrahydroquinoline and the and delocalized the delocalized 2-(20-pyridyl)quinoline. 2-(2’-pyridyl)quinoline. Both theBoth ligands the ligands react the chiral pinene-derived ligand (5S,7S)-5,7-methane-6,6-dimethyl-2-(pyridin-2-yl)-0 with5,6,7,8-tetrahydroquinolinereact [PtRwith2 (DMSO)[PtR2(DMSO)2] (R2 =] (R Me, = andMe, Ph) Ph) inthe the indelocalized the same same way way as2-(2’-pyridyl)quinoline. 6-substitutedas 6-substituted 2,2 2,2’-bipyridines:-bipyridines: Both the 2- ligands (22-(2’-pyridyl)quinoline0-pyridyl)quinoline gave gave the the mononuclear mononuclear rollover rollover complex complex11 11[ [37],37], whereas whereas thethe chiralchiral react with [PtR2(DMSO)2] (R = Me, Ph) in the same way as 6-substituted 2,2’-bipyridines: pinene-derived ligandligand (5S,7S)-5,7-methane-6,6-dimethyl-2-(pyridin-2-yl)-5,6,7,8-tetrahy-(5S,7S)-5,7-methane-6,6-dimethyl-2-(pyridin-2-yl)-5,6,7,8-tetrahy- 2-(2’-pyridyl)quinolinedroquinoline showed to be gave able th toe givegivemononuclear bothboth mono-mono- rollover andand dinucleardinuclear complex rolloverrollover 11 [37], complexescomplexes whereas 1212 the chiral pinene-derivedand 13 [[38]38] (Figure ligand 1010).). (5S,7S)-5,7-methane-6,6-dimethyl-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinoline showed to be able to give both mono- and dinuclear rollover complexes 12 and 13 [38] (Figure 10).

Figure 10. Pt(II) complexes 11–13.

In order toto shedshed lightlight intointo thethe delicatedelicate balancebalance between steric and electronic effects, FigureZucca andand10. Pt(II) coworkerscoworkers complexes investigatedinvestigated 11–13. thethe influenceinfluence ofof substituents substituents CH CH3,3, CF CF33,, CHCH22CHCH33,, andand OCH3,,[ [39–41],39–41], two two couples couples of substituents having similar stericsteric hindrancehindrance (CH(CH33 and CFCF33; CH CH and OCH ), but different electronic effects. For the first couple, the location of CH2CHIn 33order and OCH to shed33), but light different into theelectronic delicate effects. bala nceFor betweenthe first couple, steric andthe locationelectronic of effects, CH3 and CF3 in position 6 or 5 allows to separate, in part, electronic and steric influences (FigureZucca and11). coworkers investigated the influence of substituents CH3, CF3, CH2CH3, and OCH3, [39–41], two couples of substituents having similar steric hindrance (CH3 and CF3; CH2CH3 and OCH3), but different electronic effects. For the first couple, the location of

MoleculesMolecules 2021 2021, 26,, 26x FOR, x FOR PEER PEER REVIEW REVIEW 10 of10 59 of 59

Molecules 2021, 26, 328 10 of 58 CHCH3 and3 and CF CF3 3in in position position 66 oror 55 allowsallows toto separate,separate, in in part, part, electronic electronic and and steric steric influences influences (Figure(Figure 11). 11).

Figure 11. 6- and 5-substituted0 2,2’-bipyridines with CH3 and CF3 groups. FigureFigure 11. 11.6- and6- and 5-substituted 5-substituted 2,2 -bipyridines2,2’-bipyridines with with CH3 CHand3 CFand3 groups.CF3 groups.

The ligands were compared to unsubstituted 2,2’-bipyridine0 in the reaction with the TheThe ligands ligands were were compared compared to unsubstituted 2,22,2’-bipyridine-bipyridine in in the the reaction reaction with with the the electron-rich precursor [Pt(Me)2(DMSO)2]. When the substituent was located in position electron-rich precursor [Pt(Me)2(DMSO)2]. When the substituent was located in position 6, electron-rich6, regiospecific precursor activation [Pt(Me) of the2(DMSO) substituted2]. When ring occurredthe substituent affording was complexes located in 14 position (R = 6, regiospecificregiospecific activation activation of theof the substituted substituted ring ring occurred occurred affording affording complexes complexes14 (R = 14 CH (R3, = CH3, CF3), and no sign of activation on the unsubstituted ring was observed. The electron CF3), and no sign of activation on the unsubstituted ring was observed. The electron 3 3 CHwithdrawing, CF ), and CFno3 signsubstituent of activation in 6-CF on3-2,2’-bipyiridine the0 unsubstituted induced ring awas noteworthy observed. acceleration The electron withdrawing CF3 substituent in 6-CF3-2,2 -bipyiridine induced a noteworthy acceleration withdrawing CF3 substituent in 6-CF3-2,2’-bipyiridine induced a noteworthy acceleration of the rollover reaction, likely due to a sum of electronic and steric factors. of the Atrollover variance, reaction, with 5-CF likely3-2,2’-bipyiridine, due0 to a sum of the electronic reaction outcomeand steric was factors. independent from At variance, with 5-CF3-2,2 -bipyiridine, the reaction outcome was independent from thethe Atsteric variance, factor withrelated 5-CF to 3 the-2,2’-bipyiridine, substituent and the was reaction not regiospecific.regiospecific. outcome was Two independent isomers were from theobtained steric factor due toto related activationactivation to of theof both both substituent the the pyridine pyridine and rings ringswas (15 not(15and andregiospecific.16 ),16 however,), however, Two with with theisomers the electron- elec- were obtainedtron-withdrawingwithdrawing due to CF activation3 group,CF3 group, aof preference both a preference the pyridine for C(3)-H for C(3)-Hrings activation ( 15activation and in 16 the), in however, substitutedthe substituted with ring the ring was electron-withdrawingwasobserved observed (compound (compound CF3 15group,), with15), awith a preference 5:1 a molar 5:1 molar ratio for ratio (FigureC(3)-H (Figure 12activation) both 12) both in refluxingin in the refluxing substituted acetone acetone and ring 0 wasandtoluene. observed toluene. Operating Operating(compound with with 5-CH15 ),5-CH with3-2,23-2,2’-bipyiridine, a-bipyiridine, 5:1 molar ratio a a 1:1 (Figure1:1 molar molar 12) ratio ratio both between between in refluxing thethe isomersisomers acetone andwas toluene. observed. Operating with 5-CH3-2,2’-bipyiridine, a 1:1 molar ratio between the isomers was observed.

Figure 12. Influence of substituentsFigure 12. in Influence position 5 of and substituen 6 in 2,20-bipyridines.ts in position Adapted5 and 6 in with 2,2’-b permissionipyridines. from AdaptedOrganometallics with permis- 2015, 34, 5, 817–828. Copyrightsion (2015) from Organometallics American Chemical 2015, Society. 34, 5, 817–828. Copyright (2015) American Chemical Society. Figure 12. Influence of substituents in position 5 and 6 in 2,2’-bipyridines. Adapted with permission fromThese Organometallics data indicate 2015 thatthat, 34, anan 5, electron-poorelectron-poor 817–828. Copyright pyridine pyridine (2015) ring ring American is is more more reactive Chemicalreactive in in theSociety. the rollover rollo- verprocess; process; together together with with Skapski, Skapski, Sutcliffe, Sutcliffe, and Young’sand Young’s observation observation that electron-richthat electron-rich Pt(II) precursors [Pt(Ar) (DMSO) ] accelerate the rollover reaction [16], an electrophilic activa- Pt(II)These precursors data indicate [Pt(Ar)2 that2(DMSO)2 an electron-poor2] accelerate the py ridinerollover ring reaction is more [16], reactive an electrophilic in the rollo- tion pathway should be ruled out for these reactions. Under these conditions, the CH veractivation process; pathway together should with Skapski, be ruled Sutcliffe, out for these and reactions.Young’s observationUnder these thatconditions, electron-rich the3 CHsubstituent3 substituent showed showed to have to have no electronic no electronic influence influence on the on outcome the outcome of the of reaction. the reaction. Pt(II) precursors [Pt(Ar)2(DMSO)2] accelerate the rollover reaction [16], an electrophilic The authors also investigated the influence influence of electronic factors by analyzing proton activation pathway should be ruled out for these reactions. Underζ these conditions, the affinityaffinity data of subs substitutedtituted pyridines, and introduced thethe angleangle ζ inin [Pt(N,N)Me22] adducts CH3 substituent showed to have no electronic influence on the outcome of the reaction. (Figure 13)13) in order to have quantitative measurement of the steric requirement on the The authors also investigated the influence of electronic factors by analyzing proton0 plane of the substituted bipyridine in the intermediate N^N NˆN adducts.adducts. Unsubstituted 2,2’- 2,2 - affinity data of substituted◦ pyridines, and introduced the◦ angle ζ in [Pt(N,N)Me2] adducts bipyridine occupies 8. 8.88° moremore than than the the theoretical 90° 90 ofof a square planar coordination, (Figurehaving 13) a z in angle order of 98.8to have◦, a methylquantitative in 6-Me-2,2 measurement0-bipyridine of increasesthe steric the requirement value to 125.1 on ◦the, 0 ◦ planewhereas of the 6-CF substituted3-2,2 -bipyridine bipyridine has a in value the intermediate of 137.6 . N^N adducts. Unsubstituted 2,2’- bipyridine occupies 8.8° more than the theoretical 90° of a square planar coordination,

Molecules 2021, 26, x FOR PEER REVIEW 11 of 59

Molecules 2021, 26, 328 11 of 58 having a az anglez angle of 98.8°,of 98.8°, a methyl a methyl in 6-Me-2 in ,2’-bipyridine6-Me-2,2’-bipyridine increases the increase value tos 125.1°, the value to 125.1°, whereas 6-CF 6-CF3-2,2’-bipyridine3-2,2’-bipyridine has a valuehas a of value 137.6°. of 137.6°.

ζ Figure 13. angle for Pt(6-R-bipy)Me 2 complexes. Figure 13. ζ angleζ for Pt(6-R-bipy)Me complexes. FigureOn 13. the whole, angle fortaking Pt(6-R-bipy)Me account2 of the2 complexes.irreversible nature of the reaction (due to me- thaneOn release), the whole, it can taking be deduced account that of the a substituent irreversible in nature position of the 6, reactiondue to destabilization (due to methane of therelease), adduct,On it the can accelerates whole, be deduced thetaking rollover that aaccount substituent reaction, of yieldingthe in position irrevers regioselective 6,ible due tonature destabilization C(3)− Hof bondthe reactionactiva- of the (due to me- thanetion.adduct, A release),CF accelerates3 substituent it the can rollover in be position deduced reaction, 6 favors that yielding thea substituent re regioselectiveaction for threein C(3)–H position reasons: bond 6, the activation. due sterically to destabilization A of destabilization of the N^N adduct, the electronically destabilization of the adduct (the ni- theCF3 substituentadduct, accelerates in position 6 the favors rollover the reaction reaction, for three yielding reasons: theregioselective sterically destabiliza- C(3)−H bond activa- trogention of theclose NˆN to the adduct, substituent the electronically is a very poor destabilization donor), the of activation the adduct of (the the nitrogenelectron closepoor tion. A CF3 substituent in position 6 favors the reaction for three reasons: the sterically C(3)–Hto the substituent bond. is a very poor donor), the activation of the electron poor C(3)–H bond. destabilization of the N^N adduct, the electronically destabilization of the adduct (the ni- The comparison of 6-methoxy- 6-methoxy-2,22,2’-bipyridine0-bipyridine with 6-ethyl-2,26-ethyl-2,2’-bipyridine0-bipyridine evidenced trogenthe non-trivial close influence inﬂuenceto the substituent of the methoxy is a substituent,subs verytituent, poor having donor), opposite the activationinductive and and of me- the electron poor C(3)–Hsomeric effects, bond. both on Pt(II)-mediated rollove rolloverr activation and on the properties properties of of result- result- ing rolloverThe comparison complexes [[37,38].37 of,38 6-methoxy-]. 2,2’-bipyridine with 6-ethyl-2,2’-bipyridine evidenced In all the cases studied with bipyridine derivatives, it was found that the most active the non-trivialIn all the cases influence studied with of the bipyridine methoxy derivatives, substituent, it was having found that opposite the most inductive ac- and me- Pt(II)tive Pt(II) precursor precursor is the is electron-rich the electron-rich [PtMe [PtMe2(DMSO)(DMSO)2] complex.] complex. The analogue The analogue phenyl phenyl deriv- someric effects, both on Pt(II)-mediated2 rollove2r activation and on the properties of result- ativederivative [PtPh [PtPh2(DMSO)2(DMSO)2] showed2] showed to be toslightly be slightly less acti lessve. active. In contrast, In contrast, the electron-poor the electron- pooring[PtCl rollover2 [PtCl(DMSO)2(DMSO) 2complexes] does2 ]not does activate not[37,38]. activate the C(3)–H the C(3)–H bond with bond the with only the exception only exception of the di-sub- of the 0 0 stituteddi-substitutedIn 6,6’-(OMe)all the 6,6 cases-(OMe)2-2,2’-bipyridine. studied2-2,2 -bipyridine. with In thisbipyridine Incase, this reaction case, deri reaction vatives,with [PtCl with it2 [PtCl(DMSO)was 2found(DMSO)2] afforded that2] af- the most active theforded rollover the rollover complex complex 17 [42],17 [42whereas], whereas under under the the same same conditions, conditions, the the electron-poor Pt(II) precursor is the electron-rich [PtMe2(DMSO)2] complex. The analogue0 phenyl deriv- [PtCl2(DMSO)(DMSO)22] ]did did not not activate activate the the C(3)–H C(3)–H bond bond of ofthe the mono-substituted mono-substituted 6-OMe-2,2’-bi- 6-OMe-2,2 - ative [PtPh2(DMSO)2] showed to be6OMe slightly less active. In contrast, the electron-poor pyridinebipyridine affording affording the the adduct adduct [PtCl [PtCl2(bpy2(bpy6OMe)], 18)],.18 Under. Under harsher harsher conditions, conditions, activation activation of [PtClaof C–H a C–H2 (DMSO)bond bond in inthe2 the] doessubstituent substituent not activate gives gives the the the cl classicalassical C(3)–H tridentate tridentate bond withcyclometalated cyclometalated the only complex exception 19 of the di-sub- (Figurestituted 1414) )[6,6’-(OMe) [40].40]. 2-2,2’-bipyridine. In this case, reaction with [PtCl2(DMSO)2] afforded the rollover complex 17 [42], whereas under the same conditions, the electron-poor [PtCl2(DMSO)2] did not activate the C(3)–H bond of the mono-substituted 6-OMe-2,2’-bipyridine affording the adduct [PtCl2(bpy6OMe)], 18. Under harsher conditions, activation of a C–H bond in the substituent gives the classical tridentate cyclometalated complex 19 (Figure 14) [40].

0 0 Figure 14. Pt(II) complexes with 6-OMe- and 6,66,6’-(OMe)-(OMe)2-2,2’-bipyridine.-2,2 -bipyridine.

The influence inﬂuence of steric factors in rollover metalationmetalation was also observed in the reaction 0 0 of 6-NH 22-2,2’-bipyridine-2,2 -bipyridine and and 6-NMe 6-NMe2-2,2’-bipyridine2-2,2 -bipyridine with with [PtMe [PtMe2(SMe2(SMe2)]22 at)]2 roomat room temper- tem- perature.ature. The The steric steric difference difference due due to tothe the meth methylyl groups groups in in the the dimethylamino dimethylamino substituent drives the reaction towards the rollover cyclometalated complex 2020 insteadinstead ofof thethe classical N^NNˆN bidentatebidentate coordinationcoordination 2121 (Figure(Figure 15 15))[ [43].43].

Figure 14. Pt(II) complexes with 6-OMe- and 6,6’-(OMe)2-2,2’-bipyridine.

The influence of steric factors in rollover metalation was also observed in the reaction of 6-NH2-2,2’-bipyridine and 6-NMe2-2,2’-bipyridine with [PtMe2(SMe2)]2 at room temperature. The steric difference due to the methyl groups in the dimethylamino substituent drives the reaction towards the rollover cyclometalated complex 20 instead of the classical N^N bidentate coordination 21 (Figure 15) [43].

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Figure 15. Behavior of 6-NH2- and 6-NMe2-2,2’-bipyiridine.0 FigureFigure 15.15. Behavior of 6-NH22- and 6-NMe 2-2,2’-bipyiridine.-2,2 -bipyiridine. Regioselectivity RegioselectivityRegioselectivity RegioselectivityRegioselectivity in in metal-mediated metal-mediated C–H C–H bond bond activation activation is is not not a a trivial trivial topic; with Regioselectivity in metal-mediated C–H bond activation is not a trivial topic; with regardregard to to cyclometalation cyclometalation reactions, reactions, compet competitionition between between different different coordination modes regard to cyclometalation reactions, competition between different coordination modes (e.g.,(e.g., five- ﬁve- vs. vs. six-membered six-membered rings, rings, bide bidentatentate vs. vs. tridentate tridentate coordination, coordination, M-C(sp M-C(sp2) vs.2) M- vs. (e.g., five- vs. six-membered rings, bidentate vs. tridentate coordination, M-C(sp2) vs. M- C(spM-C(sp3), etc.)3), etc.) may may occur. occur. C(sp3), etc.) may occur. TheThe driving driving force force of of the the cyclometalation reaction reaction is is often often not fully understood, and The driving force of the cyclometalation reaction is often not fully understood, and subtlesubtle differences differences in in the the structure structure of of the the ligand ligand or or in in reaction conditions may may frequently frequently subtle differences in the structure of the ligand or in reaction conditions may frequently drivedrive the the reaction reaction towards towards unexpected unexpected results. results. As an As example, an example, Pd(II) Pd(II) and Pt(II) and complexes Pt(II) com- drive the reaction towards unexpected results. As an example, Pd(II)0 and Pt(II) complexes areplexes able are to ableactivate to activate several several C–H bonds C–H bondsin substituted in substituted 2,2’-bipyridines. 2,2 -bipyridines. In the Incase the of case 6- are able to activate several0 C–H bonds in substituted 2,2’-bipyridines. In the case of 6- dimethylbenzyl-2,2’-bipyridineof 6-dimethylbenzyl-2,2 -bipyridine (Figure (Figure 16), three16), three different different positions positions can canbe activated, be activated, af- dimethylbenzyl-2,2’-bipyridine2 (Figure 16), three different positions can be2 activated, affordingaffording an an N^N^C(sp NˆNˆC(sp2) tridentate) tridentate complex complex with with [5,6] [5,6 ]fused fused rings rings by by C(sp C(sp2)–H)–H bond bond acti- acti- fording an N^N^C(sp3 2) tridentate complex with [5,6] fused rings by3 C(sp2)–H bond activation,vation, an NˆNˆC(spN^N^C(sp)3) tridentate tridentate complex complex with with [5 [5]] fused fused rings rings by by C(sp C(sp)–H3)–H bond bond activation, activa- vation, an N^N^C(sp3) tridentate complex with [5] fused rings2 by C(sp3)–H bond activation,and, and, thirdly, thirdly, an NˆC an cyclometalatedN^C cyclometalated rollover rollover complex complex by C(sp by)–H C(sp bond2)–H activationbond activation on the tion, and, thirdly, an N^C cyclometalated rollover complex by C(sp2)–H bond activation onpyridine the pyridine C(3) atom C(3) (Figureatom (Figure 16 species 16 species A, B, andA, B, C, and respectively) C, respectively) [31,33 ,[31,33,44].44]. Other Other 6-Alkyl- 6- on the pyridine C(3)0 atom (Figure 16 species A, B, and C, respectively) [31,33,44]. Other 6- Alkyl-and 6-benzyl- and 6-benzyl- 2,2 -bipyridines 2,2’-bipyridines show ashow similar a similar behavior behavior [33,45]. [33,45]. Alkyl- and 6-benzyl- 2,2’-bipyridines show a similar behavior [33,45].

FigureFigure 16. 16.Positions of C–H bond activation in 6-dimethylbenzyl-2,2’-bipyridine0 and resulting Pt and Pd complexes. Figure 16. PositionsPositions of ofC–H C–H bond bond activation activation in in6-dimethylbenzyl 6-dimethylbenzyl-2,2-2,2’-bipyridine-bipyridine and and resulting resulting Pt Pt and and Pd Pd complexes. complexes. InIn the the case case of of platinum(II), platinum(II), an an important important point, point, apart apart from from the bulkiness the bulkiness of the of sub- the In the case of platinum(II), an important point, apart from the bulkiness of the substituent,substituent, is the is theelectron electron density density on on the the metal: metal: electron-rich electron-rich [PtMe2(DMSO)(DMSO)22] ]and and stituent, is the electron density on the metal: electron-rich [PtMe2(DMSO)2] and [PtMe[PtMe22(SMe(SMe2)]2)]2 2complexescomplexes showed showed to tobe be the the best best starting starting material. material. The The C–H C–H bond bond activa- acti- [PtMe2(SMe2)]2 complexes showed to be the best starting material. The C–H bond activa- tionvation step step may may follow follow different different reaction reaction paths paths (see (see Chapter Section 3)3) and and in in the the case case of methyl- tion step may follow different reaction paths (see Chapter 3) and in the case of methyl- platinum(II)platinum(II) complexes, complexes, it is is expected expected to pr proceedoceed through an oxidative addition/reductive platinum(II) complexes, it is expected to proceed through an oxidative addition/reductive eliminationelimination sequence sequence [22]. [22]. In In the the solution, solution, th thee reductive reductive elimination elimination step step involves involves elimi- elim- elimination sequence [22]. In the solution, the reductive elimination step involves elimi- nationination of of methane, methane, making making the the process process irreve irreversible.rsible. When When electron electron poor poor starting starting Pt(II) Pt(II) nation of methane, making the process2− irreversible. When electron poor starting Pt(II) complexcomplex are are used, used, such such as as [PtCl [PtCl4]24−], classical, classical cyclometalation cyclometalation occurs, occurs, likely likely following following a dif- a complex are used, such as [PtCl4]2−, classical cyclometalation occurs, likely following a differentdifferent mechanism, mechanism, and and tridentate tridentate N^N^C NˆNˆC complexes complexes are are formed formed [35]. [35 ]. ferent mechanism, and tridentate N^N^C complexes are formed [35]. InIn the the case ofof palladium,palladium, thethe situation situation is is less less clear: clear: starting starting from from Pd Pd acetate, acetate, the the rollover roll- In the case of palladium, the situation is less clear: starting from Pd acetate, the roll- overreaction reaction is not is regiospeciﬁcnot regiospecific and theand NˆC the N^ rolloverC rollover is usually is usually formed formed in competition in competition with over reaction is not regiospecific and the N^C rollover is usually formed in competition withclassic classic NˆNˆC N^N^C cyclometalated cyclometalated complexes complexes (Figure (Figure 17)[ 3317)]. [33]. It should It should be noted be noted that, that, in this in with classic N^N^C cyclometalated complexes (Figure 17) [33]. It should be noted that, in thiscase, case, acetic acetic acid acid is formed is formed as a as byproduct a byproduct and and the reactionthe reaction is expected is expected to be to reversible, be reversible, as in this case, acetic acid2− is formed as a byproduct and the reaction is expected to be reversible, the case of [MCl4] derivative (M = Pd, Pt; HCl as byproduct). as in the case of [MCl4]2− derivative (M = Pd, Pt; HCl as byproduct). as in the case of [MCl4]2− derivative (M = Pd, Pt; HCl as byproduct).

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Figure 17. Cyclopalladation reactions with 6-substituted 2,2’-bipyridines. Adapted with permis- Figure 17. Cyclopalladation reactions withwith 6-substituted6-substituted 2,22,2’-bipyrid0-bipyridines.ines. AdaptedAdapted withwithpermission permission from Organometallics 2000, 19, 21, 4295–4304. Copyright (2000) American Chemical Society. fromsion fromOrganometallics Organometallics2000 ,200019, 21,, 19 4295–4304., 21, 4295–4304. Copyright Copyright (2000) (2000) American American Chemical Chemical Society. Society.

All the platinum-mediated cases reported so far regarded rollover reactions promoted by by Pt(II) Pt(II) derivatives. derivatives. A rare A rare Pt(IV) Pt(IV) rollover rollover cyclometalation cyclometalation was reported was reported by Safari by Safariand coworkers and coworkers with 6,6’-dimethyl-2,2'-bipyridine. with 6,60-dimethyl-2,20-bipyridine. The metalation The metalation occurs under occurs mild under conditions (60 °C) starting◦ from the electron poor Pt(IV) complex H2PtCl6, with the salt [(bi- mildditions conditions (60 °C) starting (60 C) from starting the electron from the poor electron Pt(IV) poor complex Pt(IV) H2 complexPtCl6, with H2 thePtCl salt6, with [(bi- pyH)2][PtCl6] as intermediate, to finally give complex [Pt(N^C)Cl3(DMF)] 22 (N^C = roll- thepyH) salt2][PtCl [(bipyH)6] as intermediate,2][PtCl6] as intermediate, to finally give to complex ﬁnally [Pt(N^C)Cl give complex3(DMF)] [Pt(NˆC)Cl 22 (N^C3(DMF)] = roll- 22over-cyclometalated(NˆC = rollover- cyclometalated6,6’-dimethyl-2,2’-bip 6,60-dimethyl-2,2yridine, DMF0-bipyridine, = dimethylformamide) DMF = dimethylfor- [46]. mamide)Worthy to [46 note,]. Worthy complex to note,22 displayed complex in22 vitrodisplayed cytotoxicity,in vitro showingcytotoxicity, a higher showing activity a higher than activitycisplatin than against cisplatin the colon against cancer the coloncell line, cancer with cell less line, toxicity with lesson normal toxicity cells. on normal cells.

4.1.2. N-Functionalized Bipyridines 0 N-functionalized 2,22,2’-- bipyridines formform aa specialspecial case of bipyridine derivatives, beingbeing unable to form the N^N NˆN chelated complex whichwhich lies at the origin of of the the rollover rollover pathway. pathway. unable to form the N^N chelated complex0 which lies at the origin of the rollover pathway.0 Three cases are of interest: 2,22,2’-bipyridine-bipyridine N-oxide, 23, and the N-methyl-2,2’-bipyri--methyl-2,2 -bipyri- N 0 24 25 dylium and N-protonated 2,22,2’-bipyridylium-bipyridylium cationscations 24 andand 25 (Figure(Figure 1818).).

N 0 Figure 18. N-functionalized 2,22,2´-bipyridines.-bipyridines. 2− 2− 0 Reaction of of [PdCl [PdCl4]42-] andand [PtCl [PtCl4]2− with4] thewith N-methyl-2,2‘-bipyridylium the N-methyl-2,2 -bipyridylium ion 24 initially ion 24 Reaction of [PdCl4]2- and [PtCl4]2− with the N-methyl-2,2‘-bipyridylium ion 24 initially initially gave the monodentate complexes 26 which were converted into the corresponding gave the monodentate complexes 26 which were converted into the corresponding rollo- rollover complexes 27 by heating (Figure 19)[47]. Whereas the ﬁnal species can be described ver complexes 27 by heating (Figure 19) [47]. Whereas the final species can be described as rollover complexes, the reaction is actually a simple metalation, analogous to those as rollover complexes, the reaction is actually a simple metalation, analogous to those dis- displayed by ligands such as 2-phenylpyridine, because it starts forming the monodentate played by ligands such as 2-phenylpyridine, because it starts forming the monodentate adducts 26, and represents a case of “pseudo-rollover” cyclometalation. An important adducts 26, and represents a case of ‘’pseudo-rollover’’ cyclometalation. An important difference towards 2-phenylpyridine2-phenylpyridine is the positive charge ofof thethe ligand,ligand, whichwhich becomesbecomes neutraldifference after towards cyclometalation. 2-phenylpyridine is the positive charge of the ligand, which becomes neutral after cyclometalation.

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2−

Figure 19. Pseudo rollover cyclometalation of the N-methyl-2,2‘-bipyridylium cation. Reprinted (re- Figuredrawn)Figure 19. by19 Pseudo permission rollover from cyclometalation Springer Nature, of theTransitionN-methyl-2,2 Met. Chem0-bipyridylium. 1985, 240, cation. 238–240. Reprinted Substitution (redrawn)of [M(bpyMe)C13] by permission and from[M(bpyMe- SpringerH)C12] Nature, (MTransition = Pd or Met.Pt; bpyMe Chem. 1985= N-methyl-2,2’-bipyridylium, 240, 238–240. Substitution ion) with N-heterocycles. Wimmer, F.L.; Wimmer, S.; Delhi, N.; Facility, S.I.; Griffith, P.; Ten, R.W.M.; of [M(bpyMe)C13] and [M(bpyMe-H)C12] (M = Pd or Pt; bpyMe = N-methyl-2,20-bipyridylium ion) Langhout, J.P.; Gowda, N.M.N.; Gowda, M.N.; Naikar, S.B. COPYRIGHT 1985. with N-heterocycles. Wimmer, F.L.; Wimmer, S.; Delhi, N.; Facility, S.I.; Griffith, P.; Ten, R.W.M.; Langhout, J.P.; Gowda, N.M.N.; Gowda, M.N.; Naikar, S.B. COPYRIGHT 1985. At the time, the authors were not able to definitely characterize the cyclometalated complexesAt the 27 time, as monomeric the authors werespecies not excluding able to definitely dimeric/oligomeric characterize structures; the cyclometalated however, in complexesa subsequent27 aspaper, monomeric the monomeric species excluding nature of dimeric/oligomeric the complex was structures;defined and however, a series of inderivatives a subsequent were paper, obtained the monomeric by means of nature substitution of the complex reactions was [48]. defined and a series of derivativesThe nature were obtainedof the mesoionic by means k of2-N,C- substitution neutral reactionsligand in [ 4827]. is interesting and worth to be commented.The nature ofThis the ligand mesoionic belongs k2-N,C- to the neutral class ligandof abnormal-remote in 27 is interesting pyridylene and worth ligand, to a bewell-documented commented. This class ligand of N belongs-heterocyclic to the classcarbenes of abnormal-remote (NHC) [49–51]. pyridylene ligand, a well-documentedIn contrast to class the of NN-methyl-2,2‘-bipyridyliu-heterocyclic carbenes (NHC)m ion, [49 2,2’-bipyridine–51]. N-oxide, 23, is a 0 0 neutralIn contrastligand with to the a Npotential-methyl-2,2 NÔ-bipyridylium chelating behavior. ion, 2,2 -bipyridine The ShahsavariN-oxide, group23, ishas a de- neutralvoted great ligand attention with a potential to the Pt(II) NÔ chelatingchemistry behavior. of this ligand. The Shahsavari Cyclometalated group has rollover devoted com- great attention− to the Pt(II) chemistry of this ligand. Cyclometalated rollover complexes of plexes of the type [PtMe(k2N,C-bipyO-H)(L)], 28, (bipyO-H=cyclometalated 2,2’-bipyri- the type [PtMe(k2N,C-bipyO-H)(L)], 28, (bipyO-H=cyclometalated 2,20-bipyridine N-oxide) dine N-oxide) were originally obtained by Puddehphatt and coworkers in 2014 [52]. The were originally obtained by Puddehphatt and coworkers in 2014 [52]. The rollover reaction, rollover reaction, in this case, starting from the electron-rich complex [PtMe2(μ-SMe2)]2 is in this case, starting from the electron-rich complex [PtMe2(µ-SMe2)]2 is fast even at room temperature,fast even at room showing temperature, that the N-bonded showing that oxygen, the N-bonded at least in theoxygen, case ofat Pt(II),least in strongly the case of

favorsPt(II), strongly rollover metalationfavors rollover (Figure metalation 20). As usual,(Figure from 20). theAs usual, starting from complex, the starting a family complex, of Figure 48. complexesa family of with complexes different with electronic different and electron steric propertiesic and steric were properties obtained by were substitution obtained by ofsubstitution the original of neutral the original ligand neutral (SMe2). ligand In contrast, (SMe2). the In rigid contrast, ligand the 1,10-phenanthroline rigid ligand 1,10-phe- Nnanthroline -oxide gave N the-oxide N-O gave chelated the N-O complex. chelated complex.

−

Figure 20. 0 N Figure 20. 60. Rollover cyclometalation ofof 2,22,2’-bipyridine-bipyridine N-oxide.-oxide. AdaptedAdapted withwith permissionpermission from from Or- Organometallicsganometallics 20142014, 33, 33, 19,, 19, 5402 5402−−5413.5413. Copyright Copyright (2014) (2014) Americ Americanan Chemical Society.Society.

AA fewfew years years later, later, complex complex28 was 28 was resumed resumed and allowed and allowed to obtain toa obtain series ofa complexesseries of com- of general formula [Pt(NˆC)Me(L)], (L = PCy3, PPh2py, P(OPh)3, Ph2PCH2PPh2). The plexes of general formula [Pt(N^C)Me(L)], (L = PCy3, PPh2py, P(OPh)3, Ph2PCH2PPh2). The biological activities of these complexes were evaluated against a panel of standard cancer biological activities of these complexes were evaluated against a panel of standard cancer cell lines, and two of them showed a potent cytotoxic activity [53]. cell lines,In the and course two ofof theirthem investigations,showed a potent Shahsavari cytotoxic andactivity coworkers [53]. also studied the oxidativeIn the addition course reactionof their investigations, of MeI to rollover Shahsavari the Pt(II) N–Oand coworkers bipyridine also derived studied rollover the oxi- complexes,dative addition comparing reaction the of rollover MeI to complexesrollover the with Pt(II) other N–O classical bipyridine cyclometalated derived rollover ligands. com- Theseplexes, results comparing will be the reported rollover in Section complexes 4.1.6. with other classical cyclometalated ligands. These results will be reported in Section 4.1.6. 4.1.3. Double Rollover Activation and Dinuclear Complexes (Delocalized Planar Systems) 4.1.3.One Double peculiarity Rollover of Activation rollover cyclometalation and Dinuclear derives Complexes from the(Delocalized uncoordinated Planar donor Sys- atom,tems) which usually is a nitrogen. This nitrogen can coordinate to a second metal center and One peculiarity of rollover cyclometalation derives from the uncoordinated donor atom, which usually is a nitrogen. This nitrogen can coordinate to a second metal center

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and promote a second rollover metalation, bridging two metals through a highly delocal- andpromoteand promotepromote a second aa secondsecond rollover rolloverrollover metalation, metalation,metalation, bridging bridgingbridging two twotwo metals metalsmetals through throughthrough a highly aa highlyhighly delocalized, delocal-delocalized, planar connection. ized,planarized, planarplanar connection. connection.connection. 0 0 InInIn addition addition addition toto to 2,2’-bipyridine,2,2’-bipyridine, 2,2’-bipyridine, 2,2 -bipyridine, otherother other relatedrelated related related ligands,ligands, ligands, ligands, suchsuch such such asas 6-Ph-2,2’-bipyridine,6-Ph-2,2’-bipyridine, as as 6-Ph-2,2’-bipyridine, 6-Ph-2,2 -bipyridine, 6,6’-6,6’- 6,6’- 0 0 0 Ph2-bipyridine, and 2,2’:6’,2’’-terpyridine (Figure 21) are able to give double rollover met- Ph6,6Ph22-bipyridine,-Ph-bipyridine,2-bipyridine, andand 2,2’:6’,2’’-terpyridine2,2’:6’,2’’-terpyridine and 2,2 :6 ,2”-terpyridine (Figur(Figur (Figureee 21)21) areare 21 )ableable are to ableto givegive to double givedouble double rolloverrollover rollover met-metalation,metalation,alation, producingproducingproducing producing planarplanar planar planar andand and and highlyhighly highly highly delocalizeddelocalized delocalized delocalized complexes.complexes. complexes. complexes. TheThe The Thebehaviorbehavior behavior behavior ofof thesethese of thesethese lig-lig- lig- andsligandsands maymaymay may be bebe becomplex,complex, complex, complex, duedue due due toto to the tothe the the prespres pres presenceenceenceence ofof of severalseveral several metalationmetalation metalationmetalation sites.sites. sites. sites.

FigureFigure 21. 21.21. Ligands LigandsLigands involved involved involved in in in double double double rollover rollover rollover cyclometalation. cyclometalation. cyclometalation.

0 Reaction of 2,2’-bipyiridine with “PtMe2” electron-rich precursors, such as ReactionReaction of 2,2ofof -bipyiridine2,2’-bipyiridine2,2’-bipyiridine with “PtMe withwith2 ”“PtMe electron-rich“PtMe2” 2”electron-rich precursors,electron-rich suchprecursors, asprecursors, [PtMe2 (DMSO)such such 2as], as [PtMeaffords22(DMSO) the mononuclear22], affords complex the mononuclear29 when the complex reaction 29 is when carried the out reaction with 1:1 is metal/ligand carried out [PtMe 2(DMSO)(DMSO)],2], affords affords the the mononuclear mononuclear complex complex 29 29when when the the reaction reaction is carried is carried out out withmolarwith 1:1 1:11:1 ratio, metal/ligand metal/ligandmetal/ligand and dinuclear molarmolar molar complex ratio,ratio, ratio, andand30 andwith dinucleardinuclear dinuclear a 2:1 metal/ligand complexcomplex complex 3030 withwith30 molar with aa 2:1 ratio2:1 a metal/ligandmetal/ligand2:1 [36 metal/ligand]. The mononu- molarmolar molar ratioclear [36]. complex The 29mononuclearcan also be isolated, complex and 29 can then also further be isolated, reacted withand then [PtMe further(DMSO) reacted] (Figure with ratio [36].[36]. The The mononuclear mononuclear complex complex 29 29 can can also also be beisolated, isolated, and and then then further2 further reacted2 reacted with with [PtMe22[PtMe). The22(DMSO)(DMSO) fact that22]] the(Figure(Figure reaction 22).22). canTheThe be factfact stopped thatthat thethe after reactionreaction the ﬁrst cancan cyclometalation bebe stoppedstopped afterafter shows thethe first thatfirst thecy-cy- [PtMe2(DMSO)2] (Figure 22). The fact that the reaction can be stopped after the first cy- clometalationsecondclometalation activation showsshows step thatthat is slower thethe secondsecond that theactivatiactivati ﬁrstonon one. stepstep isis slowerslower thatthat thethe firstfirst one.one. clometalation shows that the second activation step is slower that the first one.

FigureFigure 22. 22. SynthesisSynthesis of of mono- mono- and and dinuclear dinuclear Pt(I Pt(II)Pt(II)I) rollover rollover bipyridinebipyridine complexes.complexes. Figure 22. Synthesis of mono- and dinuclear Pt(II) rollover bipyridine complexes. 0 0 InIn contrast, contrast, thethe samesamesame reactionreactionreaction with withwith 2,2 2,2’:62,2’:6:6 ,2”-terpyridine’,2’’-terpyridine’,2’’-terpyridine (terpy) (terpy)(terpy) showed showedshowed a a doublea doubledouble C–H C–C– HrolloverH rolloverrolloverIn contrast, activation activationactivation the affording same affordingaffording reaction only onlyonly the with binuclearthethe 2,2’:6binuclearbinuclear’,2’’-terpyridine species speciesspecies [(DMSO)MePt( [(DMSO)MePt(µ-N^C-C^[(DMSO)MePt(µ-N^C-C^ (terpy)µ showed-NˆC-CˆN a -terpy-doubleNN-- C– terpy-22terpy-2HH )PtMe(DMSO)],rolloverHH)PtMe(DMSO)],)PtMe(DMSO)], activation31 (Figure affording 3131 (Figure(Figure 23). only 23).23). the binuclear species [(DMSO)MePt(µ-N^C-C^N- terpy-2H)PtMe(DMSO)], 31 (Figure 23).

0 0 FigureFigure 23.23. RolloverRollover behavior behavior of of 2,2’:6’,2’’-terpyridine. 2,22,2’:6’,2’’-terpyridine.:6 ,2”-terpyridine. In red, acti activatedactivatedvated C–H positions; in blue, blue, notnot activatedactivated C–HC–H positions.positions.

AdaptedAdapted withwith permissionpermission fromfromfrom Organometallics OrganometallicsOrganometallics 2001 20012001,,, 20 20,20,, 6, 6,6, 1148–1152. 1148–1152.1148–1152. CopyrightCopyrightCopyright (2001) (2001)(2001) American AmericanAmerican Chemical ChemicalChemical Society. Society.Society. Figure 23. Rollover behavior of 2,2’:6’,2’’-terpyridine. In red, activated C–H positions; in blue, not activated C–H positions. Adapted with permission from OrganometallicsComplexComplex 3131 isis 2001 thethe , onlyonly only20, 6, reactionreaction reaction1148–1152. productproductproduct Copyright observedobservedobserved (2001) both bothbothAmerican withwithwith aChemicalaa Pt/terpyPt/terpyPt/terpy Society. 1:1 1:11:1 and and 2:12:1 molarmolar ratio; ratio; when when a a Pt/terpyPt/terpy 1:11:1 1:1 momo molarlarlar ratioratio isis employed, employed, aa mixture mixture of of 3131 andand startingstarting [PtMe[PtMeComplex22(DMSO)(DMSO)(DMSO) 22312]] ] isis is is recoveredrecovered recoveredthe only from fromreaction from thethe the reaction reactionproduct reaction mixture.mixture. observed mixture. ThisThis both This meansmeans with means thatthat a Pt/terpy that thethe secondsecond the second1:1 roll-roll- and 2:1 overrolloverovermolar metalationmetalation ratio; metalation when inin thisthis in a thisPt/terpy casecase case isis faster isfaster 1:1 faster mo thanthan thanlar thethe ratio the firstfirst ﬁrst is oneone employed, one and,and, and, consequently,consequently, consequently, a mixture thatthat of 31 the the and central central starting pyridyl ring after cyclometalation is activated towards rollover metalation, likely due to pyridylpyridyl[PtMe2(DMSO) ringring afterafter2] cyclometalationiscyclometalation recovered from isis activateactivatethe reactiondd towardstowards mixture. rolloverrollover This metalation, metalation,means that likelylikely the second duedue toto roll- thetheover higher higher metalation electron electron in density density this case of of the theis faster formally formally than anionic the first pyridyl pyridyl one and, ligand. ligand. consequently, In In thisthis case,case, terpyridine, terpyridine, that the central pyridyl ring after cyclometalation is activated towards rollover metalation, likely due to the higher electron density of the formally anionic pyridyl ligand. In this case, terpyridine,

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aa well-known well-known tridentate tridentate ligand, ligand, acts acts as as a 2-fo 2-fold-deprotonated,ld-deprotonated, formally dianionic, highly delocalizeddelocalized planar planar bridging bridging ligand. StartingStarting from from 3131, ,substitution substitution of of DMSO DMSO with with neutral neutral ligands ligands afforded afforded a series a series of de- of rivatives,derivatives, one one of ofwhich, which, [(CO)MePt( [(CO)MePt(μ-N^C-C^µ-NˆC-CˆNN-terpy-2-terpy-2HH)PtMe(CO)])PtMe(CO)] was was demonstrated demonstrated toto be be an organoplatinumorganoplatinum polymerpolymer with with Pt—Pt Pt---Pt interactions, interactions, by by means means of of single single crystal crystal X-ray X- raystructure structure determination determination [26, 54[26,54].]. AtAt variance, variance, 6-Ph-2,2’-bipyridine 6-Ph-2,20-bipyridine showed showed a a similar similar but but more more complex complex behavior behavior [55]. [55]. ThisThis ligand isis well-knownwell-known for for its its tendency tendency to giveto give NˆNˆC N^N^C classic classic terdentate terdentate Pt(II) cyclomet-Pt(II) cy- clometalatedalated complexes complexes by reaction by reaction with electron-poorwith electron-poor Pt(II) Pt(II) precursors, precursors, such such as K as2PtCl K2PtCl4. In4. 0 Incontrast, contrast, by by reaction reaction with with [PtR [PtR2(DMSO)2(DMSO)2] (R2] =(R Ph, = Ph, Me), Me), 6-Ph-2,2 6-Ph-2,2’-bipyridine-bipyridine is able is able to give to givemono- mono-(32) and(32) dinuclear and dinuclear(33) complexes (33) complexes (Figure (Figure24). In the24). latter In the case, latter the case, ligand the shows ligand an showsunprecedented an unprecedented behavior, actingbehavior, as a acting threefold-deprotonated as a threefold-deprotonated ligand. All threeligand. Pt–C All bondsthree 2 Pt–Coriginate bonds from originate activation from of activation C(sp )–H of bonds. C(sp2)–H bonds.

0 Figure 24. Mono-Figure and 24. Mono-dinuclear and Pt(II) dinuclear rollover Pt(II) complexe rollovers with complexes phenyl-substituted with phenyl-substituted 2,2’-bipyridines. 2,2 -bipyridines.

TheThe dinuclear dinuclear complex complex 33 isis a a unique unique complexes complexes because because (i) (i) the the two two platinum platinum centers centers areare connected connected through through a a ten-electron ten-electron bridging bridging donor, donor, (ii) (ii) three three five-membered ﬁve-membered cyclomet- cyclomet- alatedalated rings rings are are assembled assembled in in the the same same comple complexx and and in in same same ligand; (iii) (iii) the the tridentate, formallyformally dianionic, systemsystem has has a a rare rare C, C, N, N, C sequence.C sequence. From From the the starting starting complexes complexes32 and 32 33, a series of novel derivatives were obtained by reaction with neutral ligands or HCl [56]. and 33, a series of novel derivatives were obtained by reaction with neutral0 ligands or HCl [56]. For comparison, it is worth noting that reaction of 6-phenyl-2,2 -bipyridine with less 2− trans electron-richFor comparison, Pt(II) precursors, it is worth suchnoting as that [PtCl reaction4] or of 6-phenyl-2,2’-bipyridine-[PtCl(Me)(SMe)2] affords with onlyless the adduct [PtCl(Me)(NˆN)] or the well-known NˆNˆC tridentate cyclometalated complex electron-rich Pt(II) precursors, such as [PtCl4]2−or trans-[PtCl(Me)(SMe)2] affords only the [Pt(NˆNˆC)Cl]. adduct [PtCl(Me)(N^N)] or the well-known N^N^C tridentate cyclometalated complex Extension of the study to 6,60-Ph -bipyridine gave mono- and dinuclear complexes [Pt(N^N^C)Cl]. 2 according to the Pt/ligand molar ratio. With one equivalent of the Pt precursor, the [Pt(L- Extension of the study to 6,6’-Ph2-bipyridine gave mono- and dinuclear complexes 2H)(DMSO)] complex, 34, is obtained; in this case, the twofold deprotonated ligadopts according to the Pt/ligand molar ratio. With one equivalent of the Pt precursor, the [Pt(L- a CˆNˆC coordination. The reaction with two equivalents of Pt(II) produces the dinu- 2H)(DMSO)] complex, 34, is obtained; in this case, the twofold deprotonated ligadopts a clear complexes [Pt (L-4H)(DMSO) ], 35. In addition, this complex appears unique under C^N^C coordination.2 The reaction with2 two equivalents of Pt(II) produces the dinuclear several points of view. Its synthesis involves activation of four C–H bonds, with four complexes [Pt2(L-4H)(DMSO)2], 35. In addition, this complex appears unique under sev- cyclometalation reactions. In the complex, a fourfold deprotonated 6,60-Ph -bipyridine (for- eral points of view. Its synthesis involves activation of four C–H bonds,2 with four cy- mally tetra anionic) bridges two Pt-DMSO fragments acting as a planar, highly delocalized clometalationCˆNˆC-CˆNˆC reactions. 12-electron In donorthe comple [57]. x, a fourfold deprotonated 6,6’-Ph2-bipyridine (for- mallyA tetra ﬁfth anionic) analogous bridges ligand, two 6,6 Pt-DMSO000-Dimethyl-2,2 fragments0:60,2”:6”,2 acting 000as-quaterpyridine, a planar, highly wasdelocal- not ized C^N^C-C^N^C 12-electron donor [57]. studied with “PtR2” precursors, but only with PtCl2 affording the rollover tridentate complexA fifth36 (Figureanalogous 25)[ ligand,58]. 6,6’’’-Dimethyl-2,2’:6’,2’’:6’’,2’’’-quaterpyridine, was not studied with “PtR2” precursors, but only with PtCl2 affording the rollover tridentate complex 36 (Figure 25) [58].

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Figure 25. Pt(II) quaterpyridine rollover complex 36. Reprinted (redrawn) from Polyhedron 2014, 81, 188–195. Adamski, A.; Wałȩsa-Chorab, M.; Kubicki, M.; Hnatejko, Z.; Patroniak, V. Absorption Figure 25.25. Pt(II)Pt(II) quaterpyridinequaterpyridine rollover complex 36.. Reprinted (redrawn) from PolyhedronPolyhedron 20142014,, spectra, luminescence properties, and electrochemical behavior of Mn(II), Fe(III), and Pt(II) com- 8181,, 188–195. Adamski, A.; Wa Wałłe¸ȩsa-Chorab,sa-Chorab, M.; Kubicki,Kubicki, M.; Hnatejko,Hnatejko, Z.; Patroniak, V.V. AbsorptionAbsorption plexes with quaterpyridine ligand. Copyright (2014), with permission from Elsevier. spectra, luminescenceluminescence properties, properties, and and electrochemical electrochemical behavior behavior of Mn(II), of Mn(II), Fe(III), Fe(III), and Pt(II)and Pt(II) complexes com- withplexes quaterpyridine with quaterpyridine ligand. ligand. Copyright Copyri (2014),ght (2014), with permission with permission from Elsevier. from Elsevier. The double rollover cyclometalation also allowed the build-up of heterobimetallic complexesThe doubledouble by means rolloverrollover of a two-st cyclometalationcyclometalationep reaction alsoalso sequence allowedallowed e.g., thethe 37 build-up,build-up (Figure 26) ofof heterobimetallic[59].heterobimetallic complexes by meansmeans ofof aa two-steptwo-step reactionreaction sequencesequence e.g.,e.g., 3737,, (Figure(Figure 2626))[ [59].59].

Figure 26. Rollover Pt-Pd heterobimetallic complexes with 2,2´-bipyridine. Adapted with permission from Organometallics 2012, 31, 8, 2971–2977. Copyright (2012) American Chemical Society. Figure 26.26. RolloverRollover Pt-PdPt-Pd heterobimetallic heterobimetallic complexes complexes with with 2,2 2,2´-bipyridine.0-bipyridine. Adapted Adapted with with permission permis- fromsion fromOrganometallics Organometallics2012 ,201231, 8,, 31 2971–2977., 8, 2971–2977. Copyright Copyright (2012) (2012) American American Chemical Chemical Society. Society. In 2016, Aghakhanpour, Nabavizadeh, and Rashidi, following their studies on the chemistryIn 2016,2016, of Aghakhanpour,rolloverAghakhanpour complexes,, Nabavizadeh,Nabavizadeh, synthesized andand and Rashidi,Rashidi, characterized followingfollowing a series theirtheir of studiesstudies platinum(II) onon thethe chemistrycomplexes of ofbased rollover rollover on complexes,the complexes, same “double synthesized synthesized rollover and and characterizedcycloplatinated characterized a series core”a series of (Pt(µ-bpy-2 platinum(II) of platinum(II)H com-)Pt). plexesThecomplexes authors based based onfirstly the on same foundthe “doublesame that “double whereas rollover rollover cycloplatinatedthe mononuclear cycloplatinated core” rollover (Pt( core”µ-bpy-2 complex(Pt(µ-bpy-2H)Pt). [Pt(bpy- TheH)Pt). au- thorsTheH)Me(DMSO)], authors ﬁrstly found firstly 29, that is found completely whereas that the nonwhereas mononuclear emissive the inmononuclear rollover solution complex and rollover in the [Pt(bpy- solid complexH state,)Me(DMSO)], its[Pt(bpy- dinu- 29clearH)Me(DMSO)],, is completelytwofold-rollover 29 non, is completely emissiveanalogue in non[Pt solution2 (bpy-2emissive andH)Me in in solution2(DMSO) the solid and2] state,30 in exhibitsthe its solid dinuclear efficient state, twofold-its greendinu- emission under the same conditions. The other two complexes, a dinuclear (38) and a rolloverclear twofold-rollover analogue [Pt2(bpy-2 analogueH)Me [Pt2(DMSO)2(bpy-2H2])Me30 exhibits2(DMSO) efﬁcient2] 30 exhibits green emissionefficient undergreen theemissiontetranuclear same conditions.under (39) the one same The (Figure other conditions. 27), two also complexes, The exhibited other a dinuclear twobrightly complexes, (luminescence38) and a a dinuclear tetranuclear in solution (38 ()39) and oneand a (Figuresolidtetranuclear state. 27), Complex also (39) exhibited one 30 (Figure exhibits brightly 27), a structuredalso luminescence exhibited emission inbrightly solution band, luminescence andin agreement solid state. in with solution Complex the emis- and30 exhibitssolidsive state state. a located structured Complex in the 30 emission exhibitscyclometalated band, a structured in ligand. agreement emission Complexes with band, the 38 emissivein and agreement 39, however, state with located showthe inemis- theun- cyclometalatedstructuredsive state located emission ligand. in thebands, Complexes cyclometalated indicating38 and aligand. larg39, however,e amountComplexes show of MLCT 38 unstructured and in39 their, however, emissionemissive show bands,states un- indicatingstructured[60]. aemission large amount bands, of indicating MLCT in their a larg emissivee amount states of MLCT [60]. in their emissive states [60].

Figure 27. Di- and and tetranuclear tetranuclear luminescent rollover complexes 3838 and 39.. Reprinted Reprinted (redrawn) fromfrom J. Organomet.Organomet. Chem. Chem.,2016 2016,, 819 ,819, 216–227. 216–227. Aghakhanpour, Aghakhanpo R.B.;ur, Nabavizadeh,R.B.; Nabavizadeh, S.M.; Rashidi,S.M.; Rashidi, M. Newly M. Figure 27. Di- and tetranuclear luminescent rollover complexes 38 and 39. Reprinted (redrawn) from Newly designed luminescent di- and tetranuclear double rollover cycloplatinated(II) complexes. designedJ. Organomet. luminescent Chem., di- 2016, and 819, tetranuclear 216–227. double Aghakhanpo rolloverur, cycloplatinated(II) R.B.; Nabavizadeh, complexes. S.M.; Rashidi, Copyright M. Copyright (2016), with permission from Elsevier. (2016),Newly withdesigned permission luminescent from Elsevier. di- and tetranuclear double rollover cycloplatinated(II) complexes. Copyright (2016), with permission from Elsevier. Later, the series of dinuclear complexes was extended, with the synthesis of a series of complexes with the same Pt(µ-bpy-2H)Pt core, namely [(L)(L’)Pt(µ-bpy-2H)Pt(L)(L)],

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40 (L = CF3COO, Cl, Br, I; L’ = PR3), which showed that the double rollover cycloplatinated core is “a highly versatile and tunable platform for the construction of emissive materials” [61]. The emission behavior of these rollover species was found to be different from that of their correspondent classic cyclometalated complexes, with a high dependence of the emission color on the nature of the ancillary ligands.

4.1.4. Gas Phase Studies Investigations in the gas phase on rollover reactions, by means of MS spectrometry and DFT computational methods, went ahead in parallel with investigations in solution. It is interesting to observe that the two fields developed almost independently for years. The first studies involving a rollover cyclometalation in the gas-phase were presented by Bursey and coworkers in 1983, which, investigating osmium and ruthenium bipyridine complexes by means of FAB and FD mass spectrometry, reported the formation of [Os(bipy)(bipy-H)]+ and [Ru(bipy)(bipy-H)]+ rollover complexes [62,63]. After several years, during which other papers reported results not clearly connected to rollover behaviors, this chemistry was resumed in the period from 2008 to 2012 by H. Schwarz and coworkers, in particular B. Butschke, at the TU Berlin laboratory. Schwarz, Butschke, and coworkers gave a fundamental contribution to the understanding of the rollover reaction, beyond the gas-phase behavior. The Schwarz group extensively studied the rollover chemistry in the gas phase by means of mass spectrometric techniques in conjunction with DFT calculations. Their study also permitted a detailed analysis of the fundamental factors governing the rollover reaction and are well summarized in their 2012 review on the subject [7]. This review provides a quite complete overview of the gas-phase studies, so we will shortly discuss this topic, sending back to this review for an in-depth examination. Firstly, Schwarz and coworkers investigated the gas-phase behavior of the cationic + species [Pt(bipy)((CH3)2S)] , which loses CH4 and (CH3)2S to give the cyclometalated rollover species [Pt(bipy-H)]+ [64]. Labeling experiments, supplemented by DFT computations, shed light into the rollover reaction path in the gas phase: In the course of the reaction, a hydrogen atom from the bipyridine C(3)-position is combined with the coordinated methyl group to form CH4. + In addition, the thermal reactions of the rollover cation [Pt(bipy-H)] with (CH3)2S result in an unusual dehydrogenative C-C coupling of the two methyl groups to form C2H4. The experiments also gave evidence for the reversibility of the rollover process. The conversion of (CH3)2S to C2H4 is of interest because it may serve as a model for mechanistic insight in the dehydrosulfurization of sulfur-containing hydrocarbons. In order to obtain deeper insight into the gas phase behavior, the IMR (ion/molecule reaction) of [Pt(bipy−H)]+ with a series of thioethers and thiols was investigated, finding that the rollover-coordinated bipyridine has an active role in hydrogen transfer from the thioether ligand in the course of dehydrosulfurization reaction [65]. The authors conclude that the bipyridine ligand plays an active role, acting as an acceptor in the initial hydrogen transfer from the thioether ligand to the (NˆC)Pt+ core, a peculiar behavior of rollover cyclometalated complex, not showed by classical analogues. The study was extended to collision-induced fragmentation in the gas-phase of the + + cationic complexes [Pt(CH3)(L)] and[Pt(CD3)(L)] (with L = nitrogen-bidentate ligands including 2,20-bipyridine) and their thermal reactions with a series of deuterium-labeled benzenes. At variance with phenanthroline and bipyrimidine complexes, whose dissocia- tions gave the preferential formation of neutral PtCH2 and protonated heterocyclic ligands, the bipyridine complex favors loss of methane through a rollover cyclometalation process + + ([Pt(bipy)CH3] →[Pt(bipy-H)] + CH4)[66]. The gas-phase studies continued with the investigation on the ion–molecule reactions of rollover-cyclometalated [Pt(bipy-H)]+ with alkyl ethers in the gas-phase, in comparison with corresponding reactions with sulfur analogues [67,68]. Furthermore, the gas- Molecules 2021, 26, x FOR PEER REVIEW 19 of 59

The gas-phase studies continued with the investigation on the ion–molecule reac- Molecules 2021, 26, 328 tions of rollover-cyclometalated [Pt(bipy-H)]+ with alkyl ethers in the gas-phase, in19 com- of 58 parison with corresponding reactions with sulfur analogues [67,68]. Furthermore, the gas- phase ion/molecule reactions of the cationic cyclometalated species [Pt(bipy–H)]+ with chloromethanes CH4-nCln (n = 1–4), lead to a platinum-mediated C–C bond formation [69]. phase ion/molecule reactions of the cationic cyclometalated species [Pt(bipy–H)]+ with Investigations on thermal ion/molecule reactions of a series of cyclometalated Pt(II) chloromethanes CH Cln (n = 1–4), lead to a platinum-mediated C–C bond formation [69]. complexes [Pt(L–H)]4-n+ (L = 2,2’-bipyridine, 2-phenylpyridine (phpy), 7,8-benzoquinoline Investigations on thermal ion/molecule reactions of a series of cyclometalated Pt(II) (bq)) with branched and linear alkanes showed that only the rollover complex undergo complexes [Pt(L–H)]+ (L = 2,20-bipyridine, 2-phenylpyridine (phpy), 7,8-benzoquinoline hydrogen-atom transfer from the alkane to the coordinated carbon of the cyclometalated (bq)) with branched and linear alkanes showed that only the rollover complex undergo pyridine, followed by ring rotation. DFT calculations were used to elucidate reaction path- hydrogen-atom transfer from the alkane to the coordinated carbon of the cyclometalated pyridine,ways and followedeffects of bydifferent ring rotation. ligands on DFT the calculations course of the were reactions used to [70]. elucidate The main reaction pro- pathwayscesses correspond and effects to elimination of different of ligands H2 and on alkenes. the course For of all the three reactions cyclometalated [70]. The maincom- plexes, loss of C2H4 from C2H6 dominates over H2 elimination; however, the mechanisms processes correspond to elimination of H2 and alkenes. For all three cyclometalated com- of the rollover complex significantly differ for the reactions of classical cyclometalated plexes, loss of C2H4 from C2H6 dominates over H2 elimination; however, the mechanisms complexes.of the rollover In the complex case of signiﬁcantly the rollover differ complex, for the a double reactions hydrogen of classical atom cyclometalated transfer from C2H6 to the cationic [Pt(bipy-H)]+ is followed by internal ring rotation in a retro-rollover complexes. In the case of the rollover complex, a double hydrogen atom transfer from C2H6 process,to the cationic affording [Pt(bipy- [Pt(H)(bipy)]H)]+ is followed+, for the by phpy internal and ringbq complexes, rotation in the a retro-rollover cyclometalated process, pat- ternaffording is preserved [Pt(H)(bipy)] to give+, for[Pt(H the2)(L– phpyH) andspecies. bq complexes,This observation the cyclometalated indicates that pattern different is reaction mechanisms are operating in the dehydrogenation of C2H6: only the (bipy-H) roll- preserved to give [Pt(H2)(L–H) species. This observation indicates that different reaction overmechanisms ligand can are return operating to a bidentate in the dehydrogenation N, N’-coordination of Cmode2H6: after only the the hydrogen (bipy-H) transfer, rollover followingligand can a returnretro-ro tollover a bidentate pathway. N, N0-coordination mode after the hydrogen transfer, followingIn a systematic a retro-rollover investigation, pathway. a comparison of the gas-phase fragmentation of nickel, palladium,In a systematic and platinum investigation, [M(bipy)X] a comparison+ cationic ofcomplexes the gas-phase (X = fragmentationCH3, F, Cl, Br, of I, nickel, OAc) + palladium,showed that and upon platinum collision-induced [M(bipy)X] cationic dissoci complexesation (CID), (X = CHonly3, F,the Cl, Br,platinum I, OAc) showedspecies + + ++ [Pt(bipy)CHthat upon collision-induced3] and [Pt(bipy)Cl] dissociationgave rollover (CID), cyclometalation, only the platinum whereas species [Pt(bipy)CH[Pd(bipy)CH33]] + + + + and [Pt(bipy)Cl][Ni(bipy)CHgave3] gave rollover homolytic cyclometalation, cleavage of whereas metal-CH [Pd(bipy)CH3 bond. On3] theand whole, [Ni(bipy)CH the obser-3] vationsgave homolytic suggest that cleavage platinum of metal-CH is superior3 bond. to palladium On the and whole, nickel the for observations rollover metalation. suggest Mechanisticthat platinum considerations, is superior to based palladium on experimental and nickel and for rolloverDFT data, metalation. were reported Mechanistic in Chap- terconsiderations, 3 [21]. based on experimental and DFT data, were reported in Section3[21]. Gas-phase studies studies were were also also performed performed with with the the intention intention to shed to shed light light into intothe roll- the overrollover catalytic catalytic activity activity of an of (h an6-arene)RuCl(N^N) (h6-arene)RuCl(NˆN) complex complex (N^N = (NˆN 2-(pyrimidin-4-yl)pyr- = 2-(pyrimidin-4- yl)pyridine-typeidine-type ligands) ligands) [71,72]. [ 71The,72 investigation]. The investigation combined combined gas phase, gas solution, phase, solution, and in-silico and studiesin-silico will studies be thoroughly will be thoroughly discussed discussed in Section in 5 Section (see Section5 (see Section5.1). 5.1). A further exampleexample ofof rolloverrollover behavior behavior in in the the gas-phase gas-phase involved involved the the fragmentation fragmentation of ofthe the dinuclear dinuclear gold gold m-oxo m-oxo complex complex41, 41 which, which liberates liberates H2O H by2O meansby means of a of twofold a twofold rollover roll- overcyclometalation cyclometalation affording affording the cationic the cationic complex complex42. (Figure 42. (Figure 28)[73 28)]. [73].

Figure 28. Rollover Au(III)Au(III) cyclometalationcyclometalation in in the the gas-phase gas-phase with with loss loss of of water. water. Adapted Adapted with with permis- per- missionsion from fromJ. Am. J. Chem.Am. Chem. Soc. 2009Soc. ,2009131,, 36, 131 13009–13019., 36, 13009–13019. Copyright Copyright (2009) American(2009) American Chemical Chemical Society. Society. 4.1.5. Protonation and Retro-Rollover 4.1.5.As Protonation commented and before, Retro-Rollover the presence of an uncoordinated nitrogen atom in 2,20- bipyridineAs commented rollover complexesbefore, the presence deeply inﬂuences of an uncoordinated the reactivity nitrogen of these atom complexes. in 2,2’-bipyr- In particular,idine rollover the complexes nitrogen atom deeply can influences be protonated the reactivity affording of new these cationic complexes. complexes In particular, where 0 the mesoionicnitrogen atom neutral can ligand be protonated bipy* (Figures affording 29 and 30new) is ancationic isomer complexes of 2,2 -bipyridine where andthe can also be described as abnormal-remote pyridylene [49–51].

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mesoionic neutral ligand bipy* (Figures 29 and 30) is an isomer of 2,2’-bipyridine and can also be described as abnormal-remote pyridylene [49–51].

Molecules 2021, 26, x FOR PEER REVIEW 20 of 59 Molecules 2021, 26, x FOR PEER REVIEW 20 of 59

Figure 29. Resonance structures of the mesoionic (or abnormal-remote pyridylene) ligand bipy*.

Molecules 2021, 26, 328 20 of 58 Protonation of [Pt(bipy-H)Me(L)] complexes (L = DMSO, PPh3, PCy3, etc.) with [18- mesoionic neutral neutral ligand ligand bipy* bipy* (Figures (Figures 29 and 29 and30) is 30) an isisomer an isomer of 2,2’-bipyridine of 2,2’-bipyridine and can and can crown-6-H3O][BF4] produced a series of stable pyridylenes [Pt(bipy*)(Me)(L)]+. These cat- also bebe described described as as abnormal-remote abnormal-remote pyridylene pyridylene [49–51]. [49–51]. ionic species in solution follow a retro-rollover reaction, affording the corresponding N^N chelated complexes [Pt(bipy)(Me)(L)]+ (30). The retro-rollover process corresponds to an isomerization process; the reaction proceeds at different rates depending on the nature of the phosphane ligand, with the most basic PCy3 providing the fastest reaction. The mesoionic species [Pt(bipy*)(Me)(L)]+ contain two Pt−C bonds: the balance between the

Pt−C(sp2) and Pt−C(sp3) bond rupture is subtle, and competition is observed in the pres- Figure 29. Resonance structures of the mesoionic (or abnormal-remote pyridylene) ligand bipy*. Figureence of 29.29. strongResonance Resonance external structures structures donors of [74]. theof the mesoionic mesoionic (or abnormal-remote (or abnormal-remote pyridylene) pyridylene) ligand bipy*. ligand bipy*.

Protonation of [Pt(bipy-H)Me(L)] complexes (L = DMSO, PPh3, PCy3, etc.) with [18- Protonation of [Pt(bipy-H)Me(L)] complexes (L = DMSO, PPh3, PCy3, etc.) with [18- crown-6-H3O][BF4] produced a series of stable pyridylenes [Pt(bipy*)(Me)(L)]+. These cat- crown-6-Hionic species3 O][BFin solution4] produced follow a retro-rollovera series of stable reaction, pyridylenes affording [Pt(bipy*)(Me)(L)]+. the corresponding N^N These cat- ionicchelated species complexes in solution [Pt(bipy)(Me)(L)] follow a retro-rollover+ (30). The retro-rollover reaction, affording process corresponds the corresponding to an N^N chelatedisomerization complexes process; [Pt(bipy)(Me)(L)]the reaction proceeds+ (30). at different The retro-rollover rates depending process on the corresponds nature of to an isomerizationthe phosphane process;ligand, with the reactithe moston proceeds basic PCy at3 differentproviding rate thes dependingfastest reaction. on the The nature of themesoionic phosphane species ligand,[Pt(bipy*)(Me)(L)] with the + mostcontain basic two PtPCy−C3 bonds:providing the balance the fastest between reaction. the The mesoionicPt−C(sp2) and species Pt−C(sp [Pt(bipy*)(Me)(L)]3) bond rupture is +subtle, contain and two competition Pt−C bonds: is observed the balance in the pres-between the Ptence−C(sp of strong2) and external Pt−C(sp donors3) bond [74]. rupture is subtle, and competition is observed in the pres- enceFigure of 30. strong TheThe retro-rollover retro-rollover external donors process. process. [74].Ad Adaptedapted with with permission permission from from OrganometallicsOrganometallics 20132013, 32, ,32 2,, 2, 438–448. Copyright (2013) AmericanAmerican Chemical Society.Society.

LigandsProtonation with Multiple of [Pt(bipy- PersonalitiesH)Me(L)] complexes (L = DMSO, PPh3, PCy3, etc.) with [18- crown-6-HProtonation3O][BF 4and] produced retro-rollover a series processes of stable pyridylenesof Pt(II) rollover [Pt(bipy*)(Me)(L)]+. complexes were These also cationicachieved species with other in solution related follow ligands, a retro-rollover such as 2-(2’-pyridyl)quinoline, reaction, affording 6-methoxy)-2,2’-bi- the corresponding + NˆNpyridine, chelated and complexesthe helicene-2,2 [Pt(bipy)(Me)(L)]’-bipyridine proligand(30). The 3-(2-pyridyl)-4-aza[6]helicene retro-rollover process corresponds (Fig- to an isomerization process; the reaction proceeds at different rates depending on the ure 31). The rollover complex 43, obtained by reaction with [PtMe2(DMSO)2], reacts with nature of the phosphane ligand, with the most basic PCy providing the fastest reaction. HBF4 affording the corresponding protonated species 44 [75].3 The protonation reaction is + − Thereversible mesoionic due to species acid/base [Pt(bipy*)(Me)(L)] switching and bothcontain the complexes, two Pt C bonds:described the as balance organometallic between Figure− 30. The2 retro-rollover− process.3 Adapted with permission from Organometallics 2013, 32, 2, thehelicenes, Pt C(sp that) andact as Pt “multifunctionalC(sp ) bond rupture switchab is subtle,le systems” and competition due to the reversible is observed tuning in the of presence438–448. Copyright of strong (2013) external Americ donorsan Chemical [74]. Society. optical and chiroptical properties: optical rotation, electronic circular dichroism, nonpo- Figure 30. The retro-rollover process. Adapted with permission from Organometallics 2013, 32, 2, Ligandslarized luminescence, with Multiple and Personalities circularly polarized luminescence. 438–448. Copyright (2013) American Chemical Society. Protonation andand retro-rollover retro-rollover processes processes of Pt(II) of Pt(II) rollover rollover complexes complexes were also were achieved also achieved with other related ligands, such0 as 2-(2’-pyridyl)quinoline, 6-methoxy)-2,2’-bi-0 withLigands other with related Multiple ligands, Personalities such as 2-(2 -pyridyl)quinoline, 6-methoxy)-2,2 -bipyridine, pyridine,and the helicene-2,2 and the helicene-2,20-bipyridine’-bipyridine proligand 3-(2-pyridyl)-4-aza[6]heliceneproligand 3-(2-pyridyl)-4-aza[6]helicene (Figure 31). (Fig- The urerollover 31).Protonation The complex rollover43 and, obtainedcomplex retro-rollover by43, reactionobtained processes with by reaction [PtMe 2of(DMSO) with Pt(II) [PtMe2 ],rollover reacts2(DMSO) with complexes2], HBF reacts4 afford- with were also achievedHBFing the4 affording corresponding with theother corresponding protonatedrelated ligands, protonated species such44 [ 75speciesas]. 2-(2’-pyridyl)quinoline, The 44 protonation [75]. The protonation reaction is6-methoxy)-2,2’-bi- reaction reversible is pyridine,reversibledue to acid/base dueand to the acid/base switching helicene-2,2 switching and both’-bipyridine theand complexes, both the proligand complexes, described 3-(2-pyridyl)-4-aza[6]helicene described as organometallic as organometallic helicenes, (Fig- urehelicenes,that 31). act asThe that “multifunctional rollover act as “multifunctional complex switchable 43, obtained switchab systems” leby systems” duereaction to the due with reversible to the[PtMe reversible tuning2(DMSO) oftuning optical2], reacts of with opticaland chiroptical and chiroptical properties: properties: optical optical rotation, rotation, electronic electronic circular circular dichroism, dichroism, nonpolarized nonpo- HBF4 affording the corresponding protonated species 44 [75]. The protonation reaction is larizedluminescence, luminescence, and circularly and circularly polarized polarized luminescence. luminescence. reversibleFigure 31. Rollover due to organometallicacid/base switching helicenes. and Adap bothted (redrawn) the complexes, with permission described from as Chem.—A organometallic helicenes,Eur. J. 2015, 21that, 1673–1681. act as “multifunctional Copyright (2015) John switchab Wiley &le Sons, systems” Inc. due to the reversible tuning of optical and chiroptical properties: optical rotation, electronic circular dichroism, nonpo- larized4.1.6. Reactivity luminescence, of Rollover and Complexes circularly polarized luminescence.

Figure 31. Rollover organometallicorganometallic helicenes.helicenes. Adapted Adapted (redrawn) (redrawn) with with permission permission from fromChem. Chem.—A A Eur. Eur.J. 2015 J. ,201521, 1673–1681., 21, 1673–1681. Copyright Copyright (2015) (2015) John John Wiley Wiley & Sons, & Sons, Inc. Inc.

4.1.6. Reactivity of Rollover Complexes Although beyond the scope of this Review, we will brieﬂy comment some aspects Figureof the reactivity31. Rollover of organometallic bipyridine Pt(II) helicenes. rollover Adap complexes.ted (redrawn) One important with permission aspect from of the Chem.—A Eur.reactivity J. 2015 of, 21 [Pt(bipy-, 1673–1681.H)Me(L)] Copyright rollover (2015) species John Wiley (L = neutral& Sons, ligand)Inc. is their manifold

4.1.6. Reactivity of Rollover Complexes

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Molecules 2021, 26, 328 Although beyond the scope of this Review, we will briefly comment some aspects21 of of 58 the reactivity of bipyridine Pt(II) rollover complexes. One important aspect of the reactivity of [Pt(bipy-H)Me(L)] rollover species (L = neutral ligand) is their manifold reactivity withreactivity electrophiles, with electrophiles, due to the duepresence to the of presence several ofnucleophilic several nucleophilic centers or centersbonds: the or bonds:unco- ordinatedthe uncoordinated nitrogen, nitrogen, the electron-rich the electron-rich platinum platinum center, center,and the and two the Pt-C two bonds. Pt-C bonds. The reac- The tivityreactivity with with acids acids has been has beendescribed described in Section in Section 4.1.5, 4.1.5being, being connected connected with the with retro-rollo- the retro- verrollover process. process. The reaction The reaction with alkyl with halides alkyl halides usually usually leads to leads oxidative to oxidative additions additions to afford to Pt(IV)afford Pt(IV)complexes. complexes. This reactivity This reactivity is also is rela alsoted related to functionalization to functionalization of the of bipyridine the bipyridine ligandsligands and and will will be betreated treated in Chapter in Section 5.2. 5.2 . Starting from the parent complex [Pt(bipy- H)Me(DMSO)],)Me(DMSO)], a a series series of of rollover rollover com- com- plexes with different electronic and steric propertiesproperties have been obtained by substitutionsubstitution of the the neutral neutral and and anionic anionic ancillary ancillary ligands. ligands. The The structural structural modifications modiﬁcations allow allow the obtain- the ob- menttainment of species of species with withan ample an ample variety variety of prop oferties properties and potential and potential applications, applications, from emis- from siveemissive materials materials to antitumor to antitumor drugs. drugs. Some mono- and dinuclear complexes with di diphosphinesphosphines have been reported earlier inin this review. Other series of mono,mono, andand dinucleardinuclear complexescomplexes with diphosphines,diphosphines, 45–48 (see FigureFigure 3232),), havehave been been reported reported by by us us [76 [76]] and and other other researchers researchers [77 ,[77,78],78], comprising comprising the thebipyridine bipyridineN-Oxide N-Oxide complex complex [Pt(NˆC)(dppm)(p-tolyl)], [Pt(N^C)(dppm)(p-tolyl)],49, analogous 49, analogous to 48, withto 48 p-tolyl, with p- in tolylplace in on place methyl. on methyl.

0 0 Figure 32. Examples of mono-Figure and 32. dinuclear Examples Pt(II) of mono- rollover and complexes dinuclear complexesPt(II) rollover of 2,2 complexes-bipyridine complexes and 2,2 of-bipyridine 2,2’-bipyridine N-oxide with diphosphinesand compounds 2,2’-bipyridine45–48 N.-oxide Ref. [76 with]—Reproduced diphosphines (redrawn) compounds by 45–48. permission Ref. [76]—Reproduced of The Royal Society (re- of Chemistry. drawn) by permission of The Royal Society of Chemistry.

Several of these complexes may be obtained from the parent rollover compoundscompounds [Pt(bipy-[Pt(bipy-HH)Me(DMSO)])Me(DMSO)] and and [Pt 22(µ-bipy-2(µ-bipy-2HH)Me(DMSO)])Me(DMSO)] by by substitution substitution reaction reaction of the neutral ligand or by reactivity of the coordi coordinatednated methyl (e.g., (e.g., by by reaction reaction with with HCl). HCl). Among thethe ampleample family family of of the the described described complexes, complexes, some some have have interesting interesting properties, properties, such suchas the as dinuclear the dinuclear double-rollover double-rollover complexes complexes40, [Pt2(µ 40-bpy-2, [Pt2H(µ-bpy-2)(X)2(PPhH)(X)3)2],2(PPh whose3)2], emission whose emissionproperties properties dependson dependson the nature the of thenature anionic of th ligande anionic X (e.g., ligand halide X (e.g., or trifluoroacetate) halide or trifluoro- [79]. acetate)The authors [79]. The proved authors that proved the halide that ligands the halide tune ligands the brightness tune the brightness of these compounds of these com- as “organicpounds as light “organic emitting light diodes emitting (OLEDs) diodes emitters”. (OLEDs) emitters”. Finally, we we may may also also mention mention auto-assembly auto-assembly of ofan anunusual unusual polynuclear polynuclear rollover rollover hy- µ dridehydride [Pt(N^C)(µ-H)] [Pt(NˆC)( -H)]4, obtained4, obtained by by reaction reaction of of [Pt(bipy- [Pt(bipy-HH)Me(DMSO)])Me(DMSO)] with with NaBH NaBH4 4[80].[80]. 4.1.7. Other Metals 4.1.7. Other Metals The iridium rollover chemistry is rather rich; as previously shown, this metal has been The iridium rollover chemistry is rather rich; as previously shown, this metal has one of the first to display rollover metalation, and the first one with 2,20-bipyridine. After been one of the first to display rollover metalation,3+ and the first one with 2,2’-bipyridine. the final characterization of [Ir(bipy)2(bipy*)] , it3+ took five years until a second iridium After the final characterization of [Ir(bipy)2+2(bipy*)] , it took five years until a second irid- rollover complex, [Ir(bipy)(bipy-H)Cl]2 , was obtained by reaction of Ir(IV) and Ir(III) ium rollover complex, [Ir(bipy)(bipy-H)Cl]22+, was obtained by reaction of Ir(IV) and Ir(III) chlorides with 2,20-bipyridine under controlled conditions [81]. chlorides with 2,2’-bipyridine under controlled conditions [81]. An interesting case of Ir(III) rollover complex, whose reactivity have implications in An interesting case of Ir(III) rollover complex, whose reactivity have implications in organic synthesis and catalysis, was reported by Periana and coworkers in 2007. Reac- organic synthesis and0 catalysis, was reported by Periana and coworkers0 in 2007. Reaction0 tion of 6-phenyl-2,2 -bipyridine with IrCl3 and, subsequently, with 4,4 -di-tert-butyl-2,2 - of 6-phenyl-2,2’-bipyridine with IrCl3 and, subsequently, with 4,4’-di-tert-butyl-2,2’-bipyr- bipyridine, afforded the rollover complex 50, from which successive reactions with ZnMe2 idine,and AgOTf afforded allowed the rollover isolation complex of therollover 50, from complex which successive51 (Figure reactions 33)[82]. with ZnMe2 and AgOTf allowed isolation of the rollover complex 51 (Figure 33) [82].

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Figure 33. Synthesis of complex 51. Adapted with permission from Organometallics 2007, 26, 9, 2137– 2140. Copyright (2007) American Chemical Society. Figure 33.33. Synthesis ofof complexcomplex51 51.. AdaptedAdapted with with permission permission from fromOrganometallics Organometallics2007 2007, 26,, 26 9,, 9, 2137– 2137–2140.2140. ComplexCopyright Copyright (2007)51 showed (2007) Americ American interestingan Chemical Chemical reactivity Society. Society. which comprehends both stoichiometric and catalytic processes. As for stochiometric reactivity, the Ir(III) complex promotes C–H Complex 51 showed interesting reactivity which comprehends both stoichiometric bondComplex activation 51 in showed benzene, interesting generating reactivity the corresponding which comprehends Ir-phenyl complex. both stoichiometric In addition, andreaction catalytic with processes. oxidants such As for as stochiometric bis(trifluoroa reactivity,cetate)iodobenzene the Ir(III) complex resulted promotes in oxy function- C–Hand catalytic bond activation processes. in benzene, As for stochiometric generating the reactivity, corresponding the Ir(III) Ir-phenyl complex complex. promotes In C–H alization of the coordinated alkyl group at room temperature. According to the authors, addition,bond activation reaction in with benzene, oxidants generating such as bis(trifluoroacetate)iodobenzene the corresponding Ir-phenyl resulted complex. in oxyIn addition, functionalizationreactionthis was withthe first oxidants of example the coordinated such of as “relatively bis(trifluoroa alkyl group efficicetate)iodobenzene atent room Ir(III)-alkyl temperature. function resulted Accordingalization in tooxy theto function- generate authors,alizationoxy functionalized this of the was coordinated the products”. first example alkyl Furthermore, of group “relatively at room th efficientis temperature.rollover Ir(III)-alkyl Ir(III) According complex functionalization alsoto the showed authors, to tothisbe generate active was the in oxy firsta functionalizedcatalytic example process of products”.“relatively promoting Furthermore, effici C–Hent Ir(III)-alkylactivation this rollover in function benzene Ir(III) complexalization in the also presenceto generate of showedoxyacids. functionalized to be active inproducts”. a catalytic Furthermore, process promoting this rollover C–H activation Ir(III) complex in benzene also in theshowed to presencebe activeTwo of inyears acids. a catalytic later, the process study promoting was extended C–H to activation three related in benzene tridentate in theligands presence 6-(4-R- of Two years later, the study was extended to three related tridentate ligands 6-(4-R- acids.phenyl)-2,2’-bipyridine, where (R = H, CMe3, OH). The ligands gave easily rollover cy- phenyl)-2,20-bipyridine, where (R = H, CMe , OH). The ligands gave easily rollover cy- clometalationTwo years later,by reactionthe study waswith extended IrCl3 3, toaffording three related the tridentate dinuclear ligands complexes 6-(4-R- clometalation by reaction with IrCl3, affording the dinuclear complexes [Ir(NˆC)Cl2(C5H5N)]2 [Ir(N^C)Cl2(C5H5N)]2 or, with a different metal to ligand molar ratio, the bis-cyclomet- or,phenyl)-2,2’-bipyridine, with a different metal where to ligand (R molar= H, CMe ratio,3, theOH). bis-cyclometalated The ligands gave complexes easily rollover52, cy- alated complexes 52, [Ir(N^N^C)(N^C)Cl] where the 6-Ph-bipyridine ligands act both as [Ir(NˆNˆC)(NˆC)Cl]clometalation by where reaction the 6-Ph-bipyridine with IrCl ligands3, affording act both as classicalthe dinuclear tridentate andcomplexes rollover[Ir(N^C)Clclassical bidentate tridentate2(C5H5 cyclometalatingN)] and2 or, rollover with a ligand differentbidentate (Figure metal cyclometalating 34). to From ligand the dinuclearmolar ligand ratio, (Figure complex the 34).bis-cyclomet- with From the 6-Ph-bipyridinealateddinuclear complexes complex the 52 corresponding , with[Ir(N^N^C)(N^C)Cl] 6-Ph-bipyridine mononuclear where complexthe correspondingtheIr(NˆC)(NˆN)Cl 6-Ph-bipyridine mononuclear2 was ligands obtained act complex both as 0 byclassicalIr(N^C)(N^N)Cl reaction tridentate 4,4 -di-2tert was and-butylbipyridine obtained rollover by bidentate reaction [83]. cyclometalating4,4’-di-tert-butylbipyridine ligand (Figure [83]. 34). From the dinuclear complex with 6-Ph-bipyridine the corresponding mononuclear complex Ir(N^C)(N^N)Cl2 was obtained by reaction 4,4’-di-tert-butylbipyridine [83].

FigureFigure 34. 34.Ir(III) Ir(III) rollover rollover complex complex51. 51. Adapted Adapted with with permission permission from fromOrganometallics Organometallics2009, 28 2009, 12,, 28, 12, 3395–3406.3395–3406. Copyright Copyright (2009) (2009) American Americ Chemicalan Chemical Society. Society. FigureYears 34. Ir(III) later, rollover Niedner-Schatteburg, complex 51. Ad Thiel,apted with and coworkerspermission reportedfrom Organometallics the rollover 2009 be-, 28, 12, Years later, Niedner-Schatteburg,5 Thiel, and coworkers reported the rollover behav- havior3395–3406. of the Copyright iridium(III) (2009) dimer Americ [(η -Cp*)IrCl(an Chemicalµ-Cl)] Society.2 with 2-(2-dialkylaminopyrimidin-4- η5 yl)pyridineior of the whoseiridium(III) rollover dimer cyclometallation [( -Cp*)IrCl(µ-Cl)] proceeds even2 with at room 2-(2-dialkylaminopyrimidin-4- temperature affording complexyl)pyridineYears53 (Figurelater, whose Niedner-Schatteburg, 35 rollover). cyclometallation Thiel, pr anoceedsd coworkers even at reported room temperature the rollover affording behav- iorcomplex of the 53 iridium(III) (Figure 35). dimer [(η5-Cp*)IrCl(µ-Cl)]2 with 2-(2-dialkylaminopyrimidin-4- η5 yl)pyridineIn order whose to get rollover mechanistic cyclometallation insights, the pr oceedsreaction even of Co, at room Rh, andtemperature Ir precursors affording [( - complexCp*)MCl(µ-Cl)] 53 (Figure2, with 35). five different 2-heteroarylpyridines was studied in the gas-phase. As reportedIn order in to Section get mechanistic 6, the “RhCp*” insights, comple the xreaction has been of widelyCo, Rh, used and asIr catalystsprecursors for [( nu-η5- Cp*)MCl(µ-Cl)]merous rollover2 ,C–H with bond five differentfunctionalization 2-heteroarylpyridines of aromatic and was heteroaromatic studied in the compounds. gas-phase. As reported in Section 6, the “RhCp*” complex has been widely used as catalysts for numerous rollover C–H bond functionalization of aromatic and heteroaromatic compounds.

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Figure 35. Ir(III) rollover complexes 53 (Reproduced (redrawn) from Ref. [27] with permission from Figure 35. Ir(III) rollover complexes 53 (Reproduced (redrawn) from Ref. [27] with permission from the Centre National the Centre National de la Recherche Scientiﬁque (CNRS) and The Royal Society of Chemistry), 54 and de la Recherche Scientifique (CNRS) and The Royal Society of Chemistry), 54 and 55 (both reproduced (redrawn) from

Ref. [84] with permission55 (both from reproducedThe Royal Society (redrawn) of Chemistry). from Ref. [84 ] with permission from The Royal Society of Chemistry). Figure 35. Ir(III) rollover complexesIn order 53 (Reproduced to get mechanistic (redrawn) insights,from Ref. [27] the wi reactionth permission of Co, from Rh, andthe Centre Ir precursors National [(η5- In the course of the study, cationic adducts [(h5-Cp*)M(Cl)(N,N’)]+ with 2-(2-dialkyl- de la Recherche ScientifiqueCp*)MCl( (CNRS) andµ-Cl)] The, withRoyal five Society different of Chemistry), 2-heteroarylpyridines 54 and 55 (both was reproduced studied in (redrawn) the gas-phase. from As aminopyrimidin-4-yl)pyrimidine2 (M = Co, Rh, Ir) were examined in the gas phase by DFT Ref. [84] with permission fromreported The Royal in Section Society6, of the Chemistry). “RhCp*” complex has been widely used as catalysts for numerous calculations and CID ESI-MS spectrometry, displaying a rollover cyclometallation at one rollover C–H bond functionalization of aromatic and heteroaromatic compounds. of the aromatic rings to give complexes analogous5 to 53. As for the+ metal influence, rollo- InIn thethe coursecourse ofof thethe study,study, cationic cationic adducts adducts [(h [(h5-Cp*)M(Cl)(N,N-Cp*)M(Cl)(N,N’)]0)]+ with 2-(2-dialkyl- ver cyclometallation proceeds easier from cobalt to rhodium to iridium: the trend follows aminopyrimidin-4-yl)pyrimidineaminopyrimidin-4-yl)pyrimidine (M(M == Co,Co, Rh,Rh, Ir)Ir) werewere examinedexamined inin thethe gasgas phasephase byby DFTDFT the stabilities of the metal–carbon bonds formed [27]. calculationscalculations andand CIDCID ESI-MS ESI-MS spectrometry, spectrometry, displaying displaying a rollovera rollover cyclometallation cyclometallation at oneat one of The Ir(III) rollover complex 53 has, as usual, an ortho nitrogen available for coordination. theof the aromatic aromatic rings rings to giveto give complexes complexes analogous analogous to 53to. 53 As. As for for the the metal metal influence, influence, rollover rollo- cyclometallationver cyclometallationThis presence proceeds gave proceeds the easier idea easier fromto extend from cobalt cobaltthe to st rhodiumudy to rhodium to the to analogous iridium: to iridium: the pyrimidine trendthe trend follows ligand,follows the 2-(2- stabilitiesthe stabilitiesdialkylaminopyrimidin-4-yl)pyrimidine. of the of metal–carbonthe metal–carbon bonds bonds formed formed [ 27The]. [27]. resulting rollover complex 54 was used to The Ir(III)Theobtain Ir(III) rollover the rolloverheterobimetallic complex complex 53 has, Ir-Pt53 has,as and usual, as Ir-Pd usual, an complexesortho an ortho nitrogennitrogen 55 by available reaction available for with coordination. for [(PhCN) coordina-2MCl 2] tion.This orpresence This K[Pt(C presence 2gaveH4)Cl gavethe3] [84]. idea the to idea extend to extend the st theudy study to the to analogous the analogous pyrimidine pyrimidine ligand, ligand, 2-(2- 2-(2-dialkylaminopyrimidin-4-yl)pyrimidine.dialkylaminopyrimidin-4-yl)pyrimidine.Ir(III) derivatives where also used The to Theresulting obtain resulting other rollover rollover bipy complexridine- complex or 54 terpyridine-based 54waswas used used to rollover complexes. The potentially N^N^N terdentate ligand 2,6-bis(7’-methyl-4’-phe- toobtain obtain the the heterobimetallic heterobimetallic Ir-Pt Ir-Pt and and Ir-Pd Ir-Pd complexes complexes 55 by reaction withwith[(PhCN) [(PhCN)2MCl2MCl22]] nyl-2’-quinolyl)pyridine reacts with IrCl3 in glycerol at reflux, coordinating either in the oror K[Pt(CK[Pt(C22H4)Cl)Cl33]][ [84].84]. Ir(III)classicalIr(III) derivativesderivatives N^N^N mode wherewhere or alsoalso as an usedused N^N^C toto obtainobtain ligand otherother (Figure bipyridine-bipy 36)ridine- as a orconsequenceor terpyridine-basedterpyridine-based of a rollover rolloverrollovercyclometallation complexes.complexes. The The of potentially one potentially latera NˆNˆNl pyridine N^N^N terdentate ring.terdentate In ligand particular, ligand 2,6-bis(7 2,6-bis(7’-methyl-4’-phe-the0-methyl-4 author obtained0-phenyl-2 the0- bis- 2+ 2 + quinolyl)pyridinenyl-2’-quinolyl)pyriditridentate complexes, reactsne with reacts [Ir(N^N^N)(N^N^C)] IrCl with3 in IrCl glycerol3 in glycerol at reflux, and at coordinating[Ir(N^N^C) reflux, coordinating] either. Inter in alia, either the the classical innew the com- NˆNˆNclassicalplexes mode N^N^N showed or asmode anto NˆNˆCbe or theas anfirst ligand N^N^C luminescent (Figure ligand 36 )an(Figure asd aredox-active consequence 36) as a consequence Ir(III)-c of a rolloveryclometalated of cyclomet-a rollover bis-tri- allationcyclometallationdentate of one complexes lateral of one pyridine [85]. latera l ring.pyridine In particular, ring. In particular, the author the obtained author theobtained bis-tridentate the bis- 2+ + complexes,tridentate complexes, [Ir(NˆNˆN)(NˆNˆC)] [Ir(N^N^N)(N^N^C)]and [Ir(NˆNˆC)2+ and2] [Ir(N^N^C). Inter alia, the2]+. Inter new complexesalia, the new showed com- toplexes be the showed first luminescentto be the first and luminescent redox-active and Ir(III)-cyclometalatedredox-active Ir(III)-cyclometalated bis-tridentate bis-tri- com- plexesdentate [85 complexes]. [85].

Figure 36. N^N^N and N^N^C coordination modes of 2,6-bis(7’-methyl-4’-phenyl-2’-quinolyl)pyridine with Ir(III). Figure 36. NˆNˆN and NˆNˆC coordination modes of 2,6-bis(7 0-methyl-40-phenyl-20- Years later, Bexon and Williams studied the reaction of iridium terpyridyl trichloride, quinolyl)pyridineFigure 36. N^N^N with and Ir(III).N^N^C coordination modes of 2,6-bis(7’-methyl-4’-phenyl-2’-quinolyl)pyridine[Ir(N^N^N)Cl with Ir(III). 3], (N^N^N = terpyridine) with three potentially terdentate N^N^C ligands Yearswith the later, 6’-phenyl-2,2’-bipyridine Bexon and Williams studied scaffold. the reactionUnder the of iridiumreaction terpyridyl conditions trichloride, used, none of [Ir(NˆNˆN)CltheYears three later,3 ligands], (NˆNˆNBexon showed and = terpyridine)Williams tendency studied withto act the three in reactionthe potentially classic of cyclometalatediridium terdentate terpyridyl NˆNˆC N^N^C trichloride, ligands mode (Fig- 0 0 with[Ir(N^N^N)Clure the 637).-phenyl-2,2 Likely3], (N^N^N due-bipyridine to = the terpyridine) steric scaffold. hindrance with Under three of thethe potentially reactionterpyridine conditions terdentate ligand, used, 6’-phenyl-2,2’-bipyr-N^N^C none ligands of the threewithidine ligandsthe 6’-phenyl-2,2’-bipyridine binds showed to the tendency metal in toa simple act scaffold. in the N^N classic Un coordinationder cyclometalated the reaction mode conditions NˆNˆC(complex mode 56 used,), (Figure whereas none 37 ofthe). 4′- the three ligands showed tendency to act in the classic cyclometalated N^N^C mode (Fig- ure 37). Likely due to the steric hindrance of the terpyridine ligand, 6’-phenyl-2,2’-bipyridine binds to the metal in a simple N^N coordination mode (complex 56), whereas the 4′-

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Molecules 2021, 26, 328 24 of 58 tolyl groups in the other two ligands promotes a rollover C–H bond activation, affording Molecules 2021, 26, x FOR PEER REVIEW 24 of 59 complexes 57 and 58 (Figure 37) [86]. Interestingly, the two new rollover complexes ex- hibitLikely intense due to luminescence the steric hindrance in the ofsolution the terpyridine at room temperature. ligand, 60-phenyl-2,2 0-bipyridine binds to the metal in a simple NˆN coordination mode (complex 56), whereas the 40-tolyl groups intolyl the groups other twoin the ligands other two promotes ligands a rolloverpromotes C–H a rollover bond activation, C–H bond affordingactivation, complexes affording 57complexesand 58 (Figure 57 and 37 58)[ (Figure86]. Interestingly, 37) [86]. Interestingly, the two new the rollover two new complexes rollover exhibitcomplexes intense ex- luminescencehibit intense luminescence in the solution in atthe room solution temperature. at room temperature.

Figure 37. Ir(III) complexes with 6’-aryl-2,2’- bipyridines.

Rollover cyclometalation of 4,4’-Me2-2,2’-bipyridine has been reported by means of a one-pot reaction with IrCl3 and a bis-trifluoromethyl-phenylpyridine (2-(3,5-bis(trifluoromethyl)phenyl)-4-methylpyridine),Figure 37. Ir(III) complexes with 66’0-aryl-2,2-aryl-2,2’- followed0-bipyridines. bipyridines. by treatment with lithium 2,4-pentanedionate. The reaction afforded three products, separated by column chromatography. The 0 0 rolloverRollover complex cyclometalation [Ir(N^C)(N^’C’)(acac)], ofof 4,44,4’-Me-Me22-2,2-2,2’-bipyridine 59, -bipyridine(N^C = cyclometalated has been reported 2-(3,5-bis(trifluoro- byby meansmeans ofof aa methyl)phenyl)-4-methylpyridine,one-pot reaction with IrCl3 andand a a bis-trifluoromethyl-phenylpyridine bis-trifluoromethyl-phenylpyridine N’^C’ = rollover cyclometalated 4,4’-Me(2-(3,5-bis(trifluoro- (2-(3,5-bis(trifluoro-2-2,2’-bipyridine)methyl)phenyl)-4-methylpyridine), was isolated albeit with a low followed yield,followed and by bycharacterized treatment treatment with withby lithium means lithium of 2,4-pentanedionate. X-ray 2,4-pentanedio- crystallog- Theraphynate. reaction The [87]. reaction afforded afforded three products, three products, separated separated by column by column chromatography. chromatography. The rollover The 0 0 complexrolloverIridium [Ir(NˆC)(Nˆcomplex and osmium [Ir(N^C)(N^’C’)(acac)],C )(acac)], polyhydrides59, (NˆC = were cyclometalated 59, also(N^C found = cyclometalated 2-(3,5-bis(trifluoromethyl)phenyl)to be able to promote 2-(3,5-bis(trifluoro- rollover C–- 0 0 0 0 H4-methylpyridine,methyl)phenyl)-4-methylpyridine, bond activation Nin ˆC2,2’-bipyridines= rollover cyclometalatedN’^C’ and =rela rolloverted heterocycles 4,4 cyclometalated-Me2-2,2 [28].-bipyridine) Reaction4,4’-Me was2-2,2’-bipyri- of the isolated iridium(V)albeitdine) was with hydrido isolated a low complex yield, albeit and with 60characterized with a low 2,2’-bipyridine yield, and by means characterized or of6-Ph-2,2’bipyridine X-ray by crystallography means of in X-ray refluxing [87 crystallog-]. tolu- eneraphy leadsIridium [87]. to rollover and osmium C–H polyhydridesbond activation, were allowing also found isolation to be able of complexes to promote 61 rollover (Figure C–H 38). 0 bondReactionIridium activation and of in6-phenyl-2,2 osmium 2,2 -bipyridines polyhydrides′-bipyridine and related were with also heterocyclesthe pentadeuteridefound to [be28 ].able Reaction complex to promote of [IrD the rollover iridium(V)5(PR3)2] re-C– 0 0 vealshydridoH bond that activation complex the generation60 inwith 2,2’-bipyridines of 2,2 the-bipyridine rollover and comp or rela 6-Ph-2,2lexted can heterocyclesbipyridine be rationalized in[28]. refluxing asReaction a pyridyl-assisted toluene of the leads irid- process,toium(V) rollover hydrido as C–Hthe corresponding bondcomplex activation, 60 with osmium allowing 2,2’-bipyridine complexe isolations or that of6-Ph-2,2’bipyridine complexeswill be described61 (Figure inin refluxingSection 38). 4.1.7. toluene leads to rollover C–H bond activation, allowing isolation of complexes 61 (Figure 38). Reaction of 6-phenyl-2,2′-bipyridine with the pentadeuteride complex [IrD5(PR3)2] re- veals that the generation of the rollover complex can be rationalized as a pyridyl-assisted process, as the corresponding osmium complexes that will be described in Section 4.1.7.

Figure 38. Synthesis of rollover complexescomplexes61 61and and62 62.. AdaptedAdapted with with permission permission from fromOrganometallics Organometal- lics2020 2020, 39,, 11,39, 2102–2115.11, 2102–2115. Copyright Copyright (2020) (2020) American American Chemical Chemical Society. Society.

0 InReaction contrast, of when 6-phenyl-2,2 the internal-bipyridine pyridine with ring the is protected, pentadeuteride as in 3,5-dimethyl-6-phenyl- complex [IrD5(PR3)2] 2,2’-bipyridine,revealsFigure 38. that Synthesis the generationthe of reaction rollover of resultedcomplexes the rollover in 61 rotati complexand on62. ofAdapted can the beexternal rationalizedwith permission pyridine as afromring, pyridyl-assisted Organometal- with a two- process,foldlics 2020 metalation,, 39 as, the11, 2102–2115. corresponding affording Copyright the osmiumC, N, (2020) C- complexesrollover-pincer American thatChemical willcomplex beSociety. described 62 (Figure in 38). Section 4.1.7. In contrast, when the internal pyridine ring is protected, as in 3,5-dimethyl-6-phenyl- 0 Osmium2,2 -bipyridine,In contrast, thewhen reaction the internal resulted pyridine in rotation ring is protected, of the external as in 3,5-dimethyl-6-phenylpyridine ring, with a two-fold2,2’-bipyridine, metalation, the reaction affording resulted the C, in N, rotati C- rollover-pinceron of the external complex pyridine62 (Figure ring, with 38). a twofold metalation, affording the C, N, C- rollover-pincer complex 62 (Figure 38).

Osmium

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OsmiumIn the same paper, reaction of the hexahydride osmium complex 63 with 2,2’-bipyridine orIn 6-substituted the same paper, 2,2’-bipyridines reaction of the hexahydride(Ph and Me substituents) osmium complex under63 refluxwith 2,2results,0-bipyridine as the analogousor 6-substituted Ir(V) 2,2complexes,0-bipyridines in rollover (Ph and C(3)–H Me substituents) bond activation under reﬂuxand formation results, as with the analo- high yieldsgous Ir(V) of complexes complexes, 64 in (Figure rollover 39). C(3)–H Mechanistic bond activation studies, andcarried formation out with with the high correspond- yields of ingcomplexes polydeuteride64 (Figure Os(VI) 39). Mechanisticcomplex, indicates studies, th carriedat the outC–H with bond the activation corresponding is not polydeu- a N-di- rectedteride process Os(VI) complex, and precedes indicates nitrogen that coordi the C–Hnation. bond The activation coordinatively is not a N-directedsaturated complex process 63and needs precedes to release nitrogen a hydrogen coordination. molecule, The thro coordinativelyugh a reductive saturated eliminat complexion process,63 needs before to reactingrelease a with hydrogen the C molecule,−H bond. throughThe resulting a reductive electrophilic elimination Os(IV) process, center before promote reacting the with hydride-mediatedthe C–H bond. Theheterolytic resulting cleavage electrophilic of the C Os(IV)−H bond. center The promoteC–H bond the selectivity hydride-mediated is consid- eredheterolytic the result cleavage of nitrogen of the C–Htrapping bond. of Thethe C–Hintermediate bond selectivity formed isby considered C–H activation the result on the of othernitrogen ring trapping [29]. of the intermediate formed by C–H activation on the other ring [29].

Figure 39. Os(IV) rollover complexes. Adapted with permission from Organometallics 2020, 39, 11,11, 2102–2115.2102–2115. Copyright (2020) American Chemical Society.

OtherOther related related heterocycles were investigated with interesting results. Reaction with 3-methyl-1-(6-phenylpyridin-2-yl)-13-methyl-1-(6-phenylpyridin-2-yl)-1H-benzimidazolium-benzimidazolium tetrafluoroborate tetrafluoroborate proceeded in a similarsimilar way way affording affording complex complex 65.. In In contrast, contrast, modification modification in in the the ligands ligands scaffolds scaffolds gives riserise to to a a drastic drastic change change in in the the behavior. behavior. Wh Whenen the the benzimidazolium benzimidazolium group group is is replaced replaced by imidazolium,imidazolium, the the absence absence of of protection protection in in the the five-membered five-membered ring allows its metalation metalation in anan abnormal abnormal position, position, producing producing the the C^N^C CˆNˆC complex 66. Analogously, protection of the 0 positionposition 3 of of 6-phenyl-2,2 6-phenyl-2,2′-bipyridine-bipyridine with with a a methyl methyl group group drives drives rollover rollover C–H C–H activation activation toto the the external external pyridine pyridine ring ring producing producing the two-fold deprotonated CˆNˆCC^N^C complex complex67 67.. AA few few other cases have been reported for rhodium, ruthenium, copper, gold, and rhenium.rhenium. In In 2006, 2006, Zuber Zuber and and Pruchnik Pruchnik showed showed that that also also rhodium rhodium might might be involved in a I rollover C–H activation process, finding that a solution of Rh I(bipy) complexes showed rollover C–H activation process, finding0 that a solution of Rh (bipy) complexes showed H/DH/D exchange exchange at at the the C(3) C(3) and and C(3’) C(3 ) positions. positions. The The observation observation of of hydride hydride signals signals in the 1 1H-NMRH-NMR spectrum spectrum strongly strongly suggests suggests oxidative oxidative addition addition of of bipyridine bipyridine C(3)-H to rhodium III throughthrough a rollovera rollover pathway, pathway, to form the Rhto hydridoform complexthe Rh [Rh(NˆN)(NˆC)(H)(CDIII hydrido complex3O)], 68, having one chelated NˆN and one rollover NˆC bipyridine ligand [88]. [Rh(N^N)(N^C)(H)(CD3O)], 68, having one chelated N^N and one rollover N^C bipyri- Rh(III) is also able to promote double rollover activation on both the pyridine dine ligand [88]. rings of 2,20-bipyridine, as shown by heating the dicationic rhodium(III) complex Rh(III) is also able to promote double rollover activation on both the pyridine rings [Rh(bipy)(CH )(H O) ][BF ] to give the solvato species [Rh(CˆC)(CD )(H O) ], with a of 2,2’-bipyridine,3 2 as3 shown4 2 by heating the dicationic rhodium(III)3 2 3complex double-rollover C(3)ˆC(30) twofold deprotonated bipyridine, 69 [89]. The same complex, at [Rh(bipy)(CH3)(H2O)3][BF4]2 to give the solvato species [Rh(C^C)(CD3)(H2O)3], with a dou- room temperature, promoted incorporation of deuterium in the coordinated methyl group. ble-rollover C(3)^C(3’) twofold deprotonated bipyridine, 69 [89]. The same complex, at An interesting case appeared in 2013, when Niedner-Schatteburg, Thiel, and coworkers room temperature, promoted incorporation of deuterium in the coordinated methyl reported the synthesis of the air stable Ru(II) complex 70, which, in the course of catalytic group. transfer hydrogenation of ketones showed to be able to switch the bidentate ligand from An interesting case appeared in 2013, when Niedner-Schatteburg, Thiel, and cowork- NˆN (neutral) to rollover NˆC (anionic, deprotonated) coordination mode, activating a C–H ers reported the synthesis of the air stable Ru(II) complex 70, which, in the course of cata- bond in the pyrimidine ring (Figure 40). The self-rollover activation of complex 70 to give lytic transfer hydrogenation of ketones showed to be able to switch the bidentate ligand

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from N^N (neutral) to rollover N^C (anionic, deprotonated) coordination mode, activating a C–H bond in the pyrimidine ring (Figure 40). The self-rollover activation of complex Molecules 2021, 26, x FOR PEER REVIEW 26 of 59 70 to give 71 placed the basis for a hydrogen transfer process, which was investigated by Molecules 2021, 26, x FOR PEER REVIEW 26 of 59 the authors and will be discussed in Section 5 [90].

Molecules 2021, 26, 328 from N^N (neutral) to rollover N^C (anionic, deprotonated) coordination mode,26 of 58 activat- ingfrom a C–HN^N bond(neutral) in the to pyrimidine rollover N^C ring (anionic (Figure, deprotonated)40). The self-rollover coordination activation mode, of complex activat- 70ing to a giveC–H 71bond placed in the the pyrimidine basis for a ring hydrogen (Figure transf 40). Theer process, self-rollover which activation was investigated of complex by the authors and will be discussed in Section 5 [90]. 7170 placedto give the 71 basis placed for athe hydrogen basis for transfer a hydrogen process, transf whicher was process, investigated which by was the investigated authors by andthe authors will be discussed and will in be Section discussed5[90]. in Section 5 [90].

Figure 40. Switch from N^N to N^C coordination mode promoted by a Ru(II) complex. Adapted from Eur. J. Inorg. Chem. 2013, 4305–4317.

Copper entered in the rollover-family in 2008 when Yang and coworkers reported Figure 40. Switch from N^N to N^C coordination mode promoted by a Ru(II) complex. Adapted the double rollover metalation of 2,2’-bipyridine in a dodeca-copper cluster. In the cluster, Figurefrom Eur. 40. SwitchJ. Inorg. from Chem NˆN. 2013 to NˆC, 4305–4317 coordination. mode promoted by a Ru(II) complex. Adapted theFigure bipy-2 40. SwitchH group from acts N^N as to a N^C twofold-deprotonated coordination mode promoted anionic by N^C-C^N a Ru(II) complex. ligand, Adapted bonding two fromfromEur. Eur. J. J. Inorg. Inorg. Chem Chem. 2013. 2013, 4305–4317., 4305–4317. CuII atomsCopper [91]. entered in the rollover-family in 2008 when Yang and coworkers reported the doubleCopperAlthough rollover entered several in metalation the rollover-familybipyridine of 2,2’-bipyridin ligands in 2008 whenweree in Yangatested dodeca-copper and with coworkers gold cluster.(III) reported derivatives, In thethe cluster, only 6,6′- Copper entered in the rollover-family0 in 2008 when Yang and coworkers reported dimethoxy-2,2doublethe bipy-2 rolloverH group metalation′-bipyridine acts as of a 2,2 twofold-deprotonated was-bipyridine activated in a dodeca-copper by means anionic of cluster.N^C-C^N a rollover In the ligand, cluster,pathway, bonding the affording, two by bipy-2the doubleH group rollover acts as metalation a twofold-deprotonated of 2,2’-bipyridin anionice in NˆC-CˆN a dodeca-copper ligand, bonding cluster. two In Cu theII cluster, CuII atoms [91]. reactionatomsthe bipy-2 [91]. withH group gold(III) acts as acetate, a twofold-deprotonated the rollover complex anionic 72 N^C-C^N by direct ligand, C–H bondingbond activation two in aceticCuII AlthoughatomsAlthough acid [91].(Figure several several 41) bipyridine bipyridine [92]. ligands ligands were were tested tested with gold(III)with gold derivatives,(III) derivatives, only 6,6 0only- 6,6′- dimethoxy-2,2Although0-bipyridine′ -bipyridineseveral bipyridine was was activated activated ligands by means bywere means tested of a rolloverof with a rollover gold pathway,(III) pathway, derivatives, affording, affording, by only 6,6 by′- reactiondimethoxy-2,2 with with gold(III) gold(III)′-bipyridine acetate, acetate, was the the rolloveractivated rollover complex by complex means72 by of72 direct aby rollover direct C–H bond C–Hpathway, activation bond affording,activation in byin aceticreaction acidacid with (Figure (Figure gold(III) 41 41))[92 [92]. ].acetate, the rollover complex 72 by direct C–H bond activation in acetic acid (Figure 41) [92].

Figure 41. The first (and only) gold rollover complex. Adapted with permission from Organometallics 2010, 29, 5, 1064–1066. Copyright (2010) American Chemical Society. Figure 41. 41.The The first first (and (and only) only) gold gold rollover rollover complex. complex. Adapted Adapted with permission with permission from Organometallics from Organometallics 2010,,29 29,, 5, 5, 1064–1066. 1064–1066. Copyright Copyright (2010) (2010) American American Chemical Chemical Society. Society. FigureThe 41. Thelast first example (and only) in gold this rollover series complex. of comp Adaptedlexes with regards permission rhenium from Organometallics and is a case of “pseudo”2010,The 29, last5, 1064–1066. rollover example in Copyrightpathways, this series (2010) of not complexes Am includingerican regards Chemical C– rheniumH Society.bond and activation. is a case of “pseudo” Deprotonation of the The last example in this series of complexes regards rhenium and is a case of rheniumrollover pathways, complex not [ReCl(N^N)(CO) including C–H bond3] activation. (N^N = 3,3’-dihydroxo-2,2’-bipyridine), Deprotonation of the rhenium com- followed by plex“pseudo” [ReCl(NˆN)(CO)The lastrollover example pathways,] (NˆN in =this 3,3 not 0series-dihydroxo-2,2 including of comp C–0-bipyridine),lexesH bond regards activation. followed rhenium byDeprotonation exposure and is toa case of the of exposure to light, affords3 the anionic complex [Re(NÔ)(CO)3Cl] 73 (NÔ = deprotonated light,rhenium affords complex the anionic [ReCl(N^N)(CO) complex [Re(NÔ)(CO)3] (N^N =Cl] 3,3’-dihydroxo-2,2’-bipyridine),73 (NÔ = deprotonated 3-hydroxo,3 followed0- by 3-hydroxo,3’-oxo-2,2’-bipyridine“pseudo” rollover pathways, not including, see Figure3 C–H 42) bond [93]. activation. The system Deprotonation was recently of used the in the exposure0 to light, affords the anionic complex [Re(NÔ)(CO)3Cl] 73 (NÔ = deprotonated oxo-2,2rhenium-bipyridine, complex [ReCl(N^N)(CO) see Figure 42)[933].] (N^N The system = 3,3’-dihydroxo-2,2’-bipyridine), was recently used in the catalytic followed by catalyticreduction ofreduction carbon dioxide of carbon [94]. dioxide [94]. 3-hydroxo,3’-oxo-2,2’-bipyridineexposure to light, affords the anionic, see complexFigure 42) [Re(NÔ)(CO) [93]. The system3Cl] was73 (NÔ recently = deprotonated used in the catalytic3-hydroxo,3’-oxo-2,2’-bipyridine reduction of carbon dioxide, see [94].Figure 42) [93]. The system was recently used in the catalytic reduction of carbon dioxide [94].

0 0 Figure 42. 42.3,3 3,3’-dihydroxo-2,2’-bipyridine-dihydroxo-2,2 -bipyridine (left) and (left) NÔ and coordination NÔ coordination mode in complex mode73 (right). in complex 73 (right). Figure 42. 3,3’-dihydroxo-2,2’-bipyridine (left) and NÔ coordination mode in complex 73 (right). 4.2. Ligands Other than Bipyridine Figure 42. 3,3’-dihydroxo-2,2’-bipyridine (left) and NÔ coordination mode in complex 73 (right). 4.2. Ligands2,20-bipyidines Other Other than canthan beBipyridine Bipyridine considered as the prototypical rollover ligands; however, a series of other ligands, mostly hererocyclic bidentate donors, have been reported as well. 4.2. Ligands2,2’-bipyidines2,2’-bipyidines Other than can can Bipyridine be be considered considered as the as theprototypical prototypical rollover rollover ligands; ligands; however, however, a se- a series of other ligands, mostly hererocyclic bidentate donors, have been reported as well. ries of2,2’-bipyidines other ligands, can mostly be considered hererocyclic as bidentatethe prototypical donors, rollover have been ligands; reported however, as well. a series of other ligands, mostly hererocyclic bidentate donors, have been reported as well.

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4.2.1. Platinum and Palladium Complexes Molecules 2021, 26, 328 27 of 58 As described in Chapter 2, the first rollover complexes regarded a non-bipyridine ligand,4.2.1. Platinum involving and 2-(2’-thienyl)pyridine Palladium Complexes Pt(II) and Pd(II) complexes [9]. Years later, in 4.2.1.1987, PlatinumAs Chassot described and and Palladium invon Chapter Zelewsky Complexes 2, the reported first rollover the sy nthesiscomplexes of a regardedseries of homoleptica non-bipyridine Pt(II) cyclometalatedligand,Asdescribed involving incomplexes Section2-(2’-thienyl)pyridine2, the with ﬁrst aromatic rollover complexesPt(II) ligands, and regarded onePd(II) of which,complexes a non-bipyridine 74, derived[9]. Years from later, 1-(2- in ligand,thienyl)pyrazole1987, Chassot involving and 2-(2 (Figure 0-thienyl)pyridinevon Zelewsky 43). The reaction Pt(II)reported and is Pd(II)the actually sy complexesnthesis a pseudo-rollover of [9 ].a Yearsseries later, of homoleptic inprocess, since Pt(II) it 1987, Chassot and von Zelewsky reported the synthesis of a series of homoleptic Pt(II) doescyclometalated not involve complexes a C–H bond with activation, aromatic butligands, requires one reactionof which, of 74trans, derived-PtCl2(SEt from2)2 with1-(2- cyclometalatedthienyl)pyrazole complexes (Figure with 43). aromatic The reaction ligands, oneis actually of which, a74 pseudo-rollover, derived from 1-(2- process, since it thienyl)pyrazolethe organolithium (Figure derivative 43). The reaction 5-(1-2-thienyl)pyrazolyl))lithium is actually a pseudo-rollover process, [95]. since it does not involve a C–H bond activation, but requires reaction of trans-PtCl2(SEt2)2 with does not involve a C–H bond activation, but requires reaction of trans-PtCl2(SEt2)2 with thethe organolithium organolithium derivative derivative 5-(1-2-thienyl)pyrazolyl))lithium 5-(1-2-thienyl)pyrazolyl))lithium [95]. [95].

Figure 43. Complex 74.

FigureAn 43. 43. Complexinteresting Complex74. 74. rollover cyclometalation involving pyrazole rings was reported a few yearsAn later. interesting A series rollover of dimethyl cyclometalation platinum(II) involving complexes pyrazole rings[PtMe was2(N^N)] reported with a several poly- fewdentate yearsAn nitrogeninteresting later. A series ligands rollover of dimethyl containing cyclometalation platinum(II) pyrazo complexesles in volvingunderwent [PtMe pyrazole2(NˆN)] rollover withrings cyclometalation several was reported whena few polydentatedissolvedyears later. in nitrogen A pyridine series ligands of at dimethyl room containing temperature platinum(II) pyrazoles underwent(R complexes = H, Ph, rollover pyrazole, [PtMe cyclometalation2(N^N)] or N-methylimidazol-2- with several poly- N whenyl,dentate Figure dissolved nitrogen 44). in The pyridine ligands resulting at room containing complexes temperature pyrazo (R75 = (L H,les Ph,= underwentpy, pyrazole, PPh3, orCO, rollover-methylimidazol- etc.) representcyclometalation rare cases when of 2-yl, Figure 44). The resulting complexes 75 (L = py, PPh , CO, etc.) represent rare six-membereddissolved in pyridine cyclometalated at room temperaturerollover rings. (R From = H, 3 Ph,the pyrazole,starting Pt(II) or N -methylimidazol-2-derivatives, oxida- cases of six-membered cyclometalated rollover rings. From the starting Pt(II) derivatives, oxidativetiveyl, Figure addition addition 44). reactionsThe reactions resulting withwith organohalides complexes organohalides afforded75 (L afforded = thepy, corresponding PPh the3, CO, corresponding etc.) Pt(IV) represent rollover Pt(IV) rare rollovercases of complexessix-membered [96 [96].]. cyclometalated rollover rings. From the starting Pt(II) derivatives, oxidative addition reactions with organohalides afforded the corresponding Pt(IV) rollover complexes [96].

Figure 44. 44.Rare Rare Pt(II) Pt(II) 6-membered 6-membered rollover rollover cyclometalated cyclometalated complexes. complexes.

Non-bipyridine rollover complexes are rare. It took almost twenty years until a newFigure Pt(II)Non-bipyridine 44. case Rare was Pt(II) reported 6-membered rollover in the complexes literature. rollover Incyclometalated are an elegantrare. It work, took complexes. Wang almost and twenty coworkers years until a new describedPt(II) case an was example reported of room in temperature the literature. rollover In C–Han elegant bond activation work, promotedWang and by coworkers de- Pt(II) (FigureNon-bipyridine 45). The adduct rollover76 is stable complexes in the solid are state rare. at ambientIt took temperature,almost twenty but only years until a new scribed◦ an example of room temperature rollover C–H bond activation promoted by Pt(II) under(FigurePt(II) 5case C45). in was solution.The reported adduct For this 76in reason, theis stable literature. from in the the six-membered In solid an elegant state NˆN at work, chelatedambient Wang complex, temperature, and a coworkers but only de- ﬁve-membered rollover cyclometalated NˆC complex was easily formed. Likely due to the notunderscribed exceptional 5 an°C example in stability solution. of 76room For, the this Pt–Ntemperature reason, bond rupture from rollover is the fast six-membered andC–H reversible. bond activation In N^N the presence chelated promoted complex, by Pt(II) a offive-membered(Figure a good 45). coordinating The rollover adduct solvent cyclometalated76 such is stable as CH 3inCN, the N^C the solid mononuclear complex state atwas rolloverambient easily complex formed.temperature,77 Likely but due only to (Stheunder = CHnot 35 CN) exceptional°C wasin solution. isolated stability and For characterized this of reason,76, the by fromPt–N X-ray diffraction.thebond six-membered rupture is fast N^N and chelated reversible. complex, In the a The authors proposed an oxidative-addition reductive-elimination pathway for the presencefive-membered of a good rollover coordinating cyclometalated solvent N^Csuch complexas CH3CN, was the easily mononuclear formed. rolloverLikely due com- to process, based on the electron-richness of the Pt center in the three-coordinate intermediate. plexthe not 77 (Sexceptional = CH3CN) stabilitywas isolated of 76 and, the characterized Pt–N bond ruptureby X-ray is diffraction. fast and reversible. In the In THF, CH2Cl2, or benzene solution, a “roll-over cyclometalation driven self-assembly pro- cesspresence atThe ambient authorsof a temperature”good proposed coordinating afforded an oxidative-additi thesolvent tetramer such complex ason CH reductive-elimination763(FigureCN, the 45 ).mononuclear The tetramer pathway rollover for com- the assemblyprocess,plex 77 (S wasbased = promotedCH on3CN) the bywas electron-richness coordination isolated ofand the characterized freeof the nitrogen Pt center atom by in inX-ray the the rollover three-coordinatediffraction. mononu- intermedi- clear complex, a typical feature of rollover complexes, which easily leads to dinuclear ate. InThe THF, authors CH2Cl proposed2, or benzene an oxidative-additi solution, a “roll-overon reductive-elimination cyclometalation driven pathway self-assem- for the species. The rollover complex 78 was fully characterized by means of NMR, elemental blyprocess, process based at ambienton the electron-richness temperature” afforded of the Pt the center tetramer in the complex three-coordinate 76 (Figure intermedi- 45). The analysis, and X-ray diffraction [24]. tetramerate. In THF, assembly CH2Cl was2, or promotedbenzene solution, by coordination a “roll-over of the cyclometalation free nitrogen atom driven in theself-assem- rollover mononuclearbly process at complex, ambient atemperature” typical feature afforded of rollover the complexes,tetramer complex which easily 76 (Figure leads 45).to dinu- The cleartetramer species. assembly The rolloverwas promoted complex by coordination78 was fully ofcharacterized the free nitrogen by means atom inof the NMR, rollover ele- mentalmononuclear analysis, complex, and X-ray a typical diffraction feature [24]. of rollover complexes, which easily leads to dinuclear species. The rollover complex 78 was fully characterized by means of NMR, elemental analysis, and X-ray diffraction [24].

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Figure 45. Self-assembly room-temperature formation of tetramer complex 78. Adapted with permission from J. Am. Chem. Figure 45. Self-assemblySelf-assembly room-temperature room-temperature formation of tetramer complex 78. Adapted with permission from J. Am. Am. Chem. Chem. Soc. 2007, 129, 11, 3092–3093. Copyright (2007) American Chemical Society. Soc. 2007, 129, 11, 3092–3093. Copyright Copyright (2007) American Chemical Society. On the basis of common mechanisms of cyclometalation reactions, the authors pro- OnOn the basis of common mechanisms of of cy cyclometalationclometalation reactions, reactions, the the authors authors pro- pro- posed an initial Pt–N bond breaking step which generates a three-coordinate rollover posed an initial Pt–N bond breaking step which generates a three-coordinate rollover complex. The electron-rich Pt(II) center promotes the oxidative addition of the ortho-C–H complex.complex. The The electron-rich electron-rich Pt(II) Pt(II) center center promotes the oxidative addition of the ortho-C–H bond on the azaindole to give a rollover Pt(IV) hydride intermediate, from which reduc- bondbond on the azaindoleazaindole toto givegive a a rollover rollover Pt(IV) Pt(IV) hydride hydride intermediate, intermediate, from from which which reductive reductive elimination of methane gave the solvato species 75 that spontaneously self-assembles tiveelimination elimination of methane of methane gave gave the the solvato solvato species species75 that75 that spontaneously spontaneously self-assembles self-assembles to to the cyclic Pt4 compound 78. tothe the cyclic cyclic Pt 4Ptcompound4 compound78 78. . Kinetic NMR analyses established a first-order decay of the adduct [Pt(N^N)Me2] KineticKinetic NMRNMR analysesanalyses established established a ﬁrst-ordera first-order decay decay of theof adductthe adduct [Pt(NˆN)Me [Pt(N^N)Me2] with2] with time in good agreement with an intramolecular cyclometalation process; the C–H withtime intime good in agreementgood agreement with an with intramolecular an intramolecular cyclometalation cyclometalation process; process; the C–H the rollover C–H rollover cleavage was found to be the rate determining step of the overall process. rollovercleavage cleavage was found was to found be the to rate be determiningthe rate determining step of the step overall of the process. overall process. Successively, the same group reported the rollover metalation of related triarylboron Successively,Successively, the same group reported the ro rolloverllover metalation of related triarylboron ligands. Additionally, in this case, rollover cyclometalation occurs very easily by reaction ligands.ligands. Additionally, Additionally, in this case, rollover rollover cyclometalation occurs very easily by reaction with Pt(II) electron rich precursors, affording the corresponding cyclometalated complex with Pt(II) electron rich precursors, afford affordinging the corresponding cyclometalated complex 79 and 80 (Figure 46). The complexes exhibit interesting phosphorescent properties, with 7979 and 80 (Figure(Figure 46)46).. The The complexes complexes exhibit exhibit interesting interesting phosphorescent properties, with unusuallyunusually long long phosphorescent phosphorescent decay decay time. time. Addi Additiontion of of fluoride ﬂuoride was was found found to to result result in a unusually long phosphorescent decay time. Addition of fluoride was found to result in a largelarge enhancement enhancement of of the the phosphorescent phosphorescent emis emissionsion intensity intensity of of the the complexes. complexes. However, However, large enhancement of the phosphorescent emission intensity of the complexes. However, complexcomplex 8080 isis not not dual dual emissive emissive as as 7979 and shows only metal-to-ligand change-transfer- change-transfer- complex 80 is not dual emissive as 79 and shows only metal-to-ligand change-transfer- basedbased phosphorescence phosphorescence [97]. [97]. based phosphorescence [97].

Figure 46. RolloverFigure complexes 46. Rollover 79 and complexes 80. Adapted79 and from80. Chem.— AdaptedA from Eur.Chem. J. 2009 A, 15 Eur., 6131–6137. J. 2009, 15 , 6131–6137. Figure 46. Rollover complexes 79 and 80. Adapted from Chem.—A Eur. J. 2009, 15, 6131–6137. AnAn uncommon uncommon case case of of rollover rollover cyclometalation, cyclometalation, resulting resulting in in a a C^C CˆC metallacycle, was An uncommon case of rollover cyclometalation, resulting in a C^C metallacycle, was reportedreported by by Rourke Rourke and coworkers. Starting Starting from from the the 14-electron 14-electron tricoordinated tricoordinated Pt(II) Pt(II) reported 81by Rourke and coworkers. Starting from the 14-electron tricoordinated Pt(II) complexcomplex 81,, stabilized stabilized by by an an agostic Pt—Pt---3HCHC interaction, the the unusual isomeric rollover complex 81, stabilized0 by an agostic Pt---3HC interaction, the unusual isomeric rollover complexescomplexes 8282 andand 82’82 werewere slowly slowly formed formed at at ambient ambient temperature temperature in in DMSO. DMSO. Starting Starting from from complexes82 and 820 ,82 a and switchable 82’ were reaction, slowly formed driven at by ambient the solvent, temperature was observed: in DMSO. in Starting CHCl from, the 82 and 82’, a switchable reaction, driven by the solvent, was observed: in CHCl3, the3 roll- 82 and 82’, a switchable reaction, driven by the solvent, was observed: in CHCl3, the rolloverrollover complex complex was was transformed transformed into into the theclassical classical cyclometalated cyclometalated complex complex 83, 83whereas, whereas in over complex was transformed into the classical cyclometalated complex 83, whereas in thein themore more polar polar solvent solvent DMSO, DMSO, the reverse the reverse reaction reaction occurs occurs regenerating regenerating the rollover the rollover com- the more polar solvent DMSO, the reverse reaction occurs regenerating the rollover complexcomplex (Figure (Figure 47). 47These). These data data have have been been expl explainedained in interms terms of of a adelicate delicate balance balance (induced (induced plexby the (Figure bulkiness 47). ofThese the tertdata-butyl have group), been expl controlledained in by terms solvent of a polaritydelicate [balance98]. (induced by the bulkiness of the tert-butyl group), controlled by solvent polarity [98]. by the bulkiness of the tert-butyl group), controlled by solvent polarity [98].

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2−

Figure 47. Switchable rollover-classical cyclometalation reaction driven by the solvent. Adapted with permission from Organometallics 2011, 30, 13, 3603–3609. Copyright (2011) American Chemical Society. Figure 47. Switchable rollover-classical cyclometalation reaction driven by the solvent. Adap Adaptedted with permission from Organometallics 2011, 30, 13, 3603–3609.3603–3609. Copyright (2011) AmericanAmerican Chemical Society. Figure 19 Another unusual and very interesting case, regarded an NHC-rollover, C^C chelated, Pd(II) complex, reported by Thiel and coworkers starting from the imidazolium salts 86 AnotherAnother unusual unusual and and very very interesting interesting case, case, regarded regarded an an NHC-rollover, NHC-rollover, C^C CˆC chelated, chelated, Pd(II)Pd(II)(Figure complex, complex, 48). reported reported by by Thiel and coworkers starting from the imidazolium salts 86

(Figure(FigureDepending 48).48). on the reaction conditions, both C^N and C^C complexes were obtained (complexesDepending 85 and on 87the). reactionTwo routes conditions, were used both for C^N the tw ando classes C^C complexes of complexes: were transmeta- obtained (complexeslation with 85the and corresponding 87). Two routes Ag-NHC were usedcomplexes for the 84 tw gaveo classes the C^N of complexes: cyclopalladated transmeta- com- lationplexes with 85, whereasthe corresponding reaction of Ag-NHC PdCl2 with complexes the imidazolium 84 gave the salts C^N produced cyclopalladated the C^C com-rollo- plexesver complexes 85, whereas 87 [99]. reaction of PdCl2 with the imidazolium salts produced the C^C rollover complexes 87 [99].

−

FigureFigure 48. 48.NHC-rollover palladium complexes. Adapted from Chem. Eur. J. 2017, 23, 14563–14575.

Depending on the reaction conditions, both CˆN and CˆC complexes were obtained (complexes 85 and 87). Two routes were used for the two classes of complexes: trans- metalationFigure 48. NHC-rollover with the corresponding palladium complexes. Ag-NHC Adapted complexes from84 Chem.—gave theEur. CˆN J., 2017 cyclopalladated, 23, 14563– complexes14575. 85, whereas reaction of PdCl with the imidazolium salts produced the CˆC Figure 48. NHC-rollover palladium complexes.2 −Adapted from Chem.—Eur. J., 2017, 23, 14563– rollover complexes 87 [99]. 14575. − TheThe rolloverrollover cyclometalationcyclometalation reaction is partiallypartially reversible.reversible. Treatment of the NˆCN^C ◦ complexcomplexThe rollover8888 withwith potassiumcyclometalationpotassium carbonatecarbonate reaction inin deuterateddeuterated is partially pyridinepyridine reversible. atat 8080Treatment °CC gavegave complexofcomplex the N^C 8989 complexwithwith aa 95%95% 88 conversionconversionwith potassium (NMR(NMR carbonate criterion),criterion), in whereaswhereas deuterated treatmenttreatment pyridine ofof89 89at withwith80 °C HClHCl gave gavegave complex evidenceevidence 89 of the presence of complex 88 (along with an intermediate specie), eventually resulting in withof the a 95%presence conversion of complex (NMR 88 criterion), (along with whereas an intermediate treatment spofecie), 89 with eventually HCl gave resulting evidence in decompositiondecomposition (Figure(Figure 4949).). Figure 60. of the presence of complex 88 (along with an intermediate specie), eventually resulting in decomposition (Figure 49).

FigureFigure 49.49. ReversibleReversible rollover reaction of the NHC-rollover palladium palladium complex complex 8989. .Adapted Adapted from from Chem.Chem.—Eur. Eur. J. 2017 J., 2017,23 23, 14563–14575. Figure 49. Reversible, ,rollover 14563–14575. reaction of the NHC-rollover palladium complex 89. Adapted from Chem.—Eur. J., 2017, 23, 14563–14575.

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The new rolloverrollover compoundscompounds showedshowed highhigh catalyticcatalytic activitiesactivities inin Suzuki–MiyauraSuzuki–Miyaura cross-coupling reactions. Catalytic processes involving rollover complexescomplexes willwill bebe treatedtreated in Sections5 5 and and6 .6. As we are seeing, rollover cyclometalated complexes may appear in different subclasses. In addition to bidentate N^C NˆC and CˆCC^C derivatives,derivatives, anotheranother interestinginteresting subclasssubclass isis that of pincer-rolloverpincer-rollover complexes. This behavior originates from from the fact that some polydentate ligands are able to switch between multiplemultiple coordinationcoordination modes.modes. A ﬁrstfirst exampleexample of pincer-rollover coordination involved the potentially tridentatetridentate ligandsligands 90––9292,, deﬁneddefined “pincer“pincer clickclick ligands”ligands” (PCL)(PCL) duedue toto theirtheir coordinativecoordinative versatility.versatility. Under a choice choice of of reaction reaction conditions, conditions, thes thesee ligands ligands can can selectivel selectivelyy behave behave as aspincer pin- certridentate tridentate or rollover or rollover bidentate bidentate ligands ligands both both with with Pd(II) Pd(II) and Pt(II) and Pt(II) metal metal precursors precursors (Fig- (ureFigure 50). 50 The). The authors authors were were able able to todemonstrate demonstrate a a“rollover “rollover switch” switch” of of kinetically kinetically formed products (i.e., rollover bidentatebidentate complexes)complexes) toto thethe thermodynamicallythermodynamically favoredfavored productsproducts (i.e., tridentate pincers) [[100].100]. As an example, the authors were able to “rollover switch” the PˆNP^N bidentate bidentate complexes complexes95 ,95 kinetically, kinetically controlled, controlled, to the to tridentate the tridentate complex complex96, which 96, iswhich the thermodynamically is the thermodynamically favored favored species species (Figure (Figure 50). 50).

Figure 50. Pincer ligands 90–9290–92 and examples of of bidentate bidentate (93), (93), pinc pincerer tridentate tridentate (94), (94), and and rollover rollover tridentate (96) (96) complexes. complexes. Ad Adaptedapted with with permission permission from from OrganometallicsOrganometallics 20092009, 28, 28, 24,, 24, 7001–7005. 7001–7005. Copyright (2009) American Chemical Society.Society.

A second case of pincer-rollover switch regardedregarded the behavior of two unsymmetrical phosphine-pyrazole PˆCˆNP^C^N pincer pincer ligands ligands (PˆCˆN (P^C^N = 1-[3-[(di- = 1-[3-[(di-tert-butylphosphino)methyl]-tert-butylphosphino)me- phenyl]-1thyl]phenyl]-1H-pyrazole,H-pyrazole, and itsand methylated its methylated analogue, analogue, PˆCˆN-Me) P^C^N-Me)97 and 9798 and). 98). In the course of thethe synthesissynthesis of palladium(II)palladium(II) complexes, starting from complex 99, the monomeric intermediate hydroxide specie speciess [Pd(P^C^N)(OH)] [Pd(PˆCˆN)(OH)] showedshowed anan unexpectedunexpected N-detachment, followedfollowed by by room room temperature temperature rollover rollover C–H C− activationH activation on the on pyrazolethe pyrazole ring, whichring, which converts converts the formally the formally anionic anionic PˆCˆN P^C^ pincerN pincer ligand ligand into a formallyinto a formally dianionic dianionic PˆCˆC rollover-pincerP^C^C rollover-pincer ligand, ligand, ﬁnally finally affording affording the dinuclear the dinuclear species species100. In100 contrast,. In contrast, with with the methylatedthe methylated analogue analogue PCN-Me, PCN-Me, norollover no rollove reactivityr reactivity was was observed observed and and the mononuclearthe mononu- complexclear complex101 was 101 isolated was isolated and characterized and characterized (Figure (Figure 51)[28 51)]. [28].

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Figure 51. Pincer ligands 97 and 98 and rollover P^C^C tridentate Pd(II) complex 100. Adapted with permission from Organometallics 2015, 34, 16, 3998–4010. Copyright (2015) American Chemi- cal Society. Figure 51.51.Pincer Pincer ligands ligands97 97and and98 and98 and rollover rollover PˆCˆC P^C^C tridentate tridentate Pd(II) complex Pd(II) complex100. Adapted 100. withAdapted permissionwith permissionA DFT from computational Organometallics from Organometallics2015 investigation, 34, 16, 2015, 3998–4010. 34, revealed 16, Copyright 3998–4010. low (2015) energy Copyright American barriers (2015) Chemical for American Society.pyrazole Chemi- C−H cal Society. activationA DFT following computational a σ-bond investigation metathesis revealed pathway, low energy in line barriers with the for experimental pyrazole C–H data. activationA few following years later, a σ-bond the same metathesis group pathway, studied inthe line hydrogenolysis with the experimental of mono- data. and dinuclear Pd(II)AA fewhydroxidesDFT years computational later, of the the same same investigation group ligands, studied 97 revealed theand hydrogenolysis 98. lowWhereas energy ofreaction mono-barriers andof forthe dinuclear pyrazoledinuclear C hy-−H activationPd(II)droxo hydroxidescomplexes following of[(P^C^N) thea σ same-bond2Pd ligands, metathesis2(µ-OH)]97 +and pathway,with98 .H Whereas2 afforded in line reaction with the thecorresponding of experimental the dinuclear dinuclear data. + hydroxohydridesA few complexes [(P^C^N) years later, [(PˆCˆN)2Pd the2(m-H)] 2samePd2+(,µ groupthe-OH)] same studiedwith reaction H2 theafforded hydrogenolysisof the the mononuclear corresponding of mono- complex dinuclear and (PCN)Pd-dinuclear + Pd(II)hydridesOH (102 hydroxides [(PˆCˆN)) resulted2Pd ofin2 (m-H)] thea rollover same, the ligands, sameactivation reaction 97 andof ofone 98 the. pyrazoleWhereas mononuclear ring,reaction complex affording of the (PCN)Pd- dinuclearthe dinuclear hy- + droxoOHspecies (102 complexes )[(PCNH)Pd](µ-H)[(PCC)Pd], resulted in[(P^C^N) a rollover2Pd activation2(µ-OH)] 103 of with, one bearing pyrazole H2 afforded two ring, different affordingthe corresponding pincer thedinuclear ligands dinuclear (P^C^N species [(PCNH)Pd](µ-H)[(PCC)Pd],+ 103, bearing two different pincer ligands (PˆCˆN and hydridesand P^C^C, [(P^C^N) Figure2 Pd52).2(m-H)] The analogous, the same reaction, reaction under of the the mononuclear same conditions, complex with (PCN)Pd- the ter- OHPˆCˆC, (102 Figure) resulted 52). The in analogousa rollover reaction, activation under of theone same pyrazole conditions, ring, withaffording the terminal the dinuclear hydroxominal hydroxo complex complex of the rollover-protected of the rollover-protected methylated methylated ligand, 101 ,ligand, did not 101 produce, did not any produce species [(PCNH)Pd](µ-H)[(PCC)Pd], 103, bearing two different pincer ligands (P^C^N hydride.any hydride. Reaction Reaction mechanisms mechanisms for the for hydrogenolysis the hydrogenolysis of the monomeric of the monomeric and dimeric and dimeric andhydroxo P^C^C, species species Figure were were 52). proposed proposed The analogous on theon basisthe reaction,basis of DFT of calculationsDFT under calculations the [same101]. conditions,[101]. with the terminal hydroxo complex of the rollover-protected methylated ligand, 101, did not produce any hydride. Reaction mechanisms for the hydrogenolysis of the monomeric and dimeric hydroxo species were proposed on the basis of DFT calculations [101].

Figure 52. 52.Synthesis Synthesis of theof the dinuclear dinuclear hydrido hydrido complex complex103. Adapted 103. Adapted from Chem. from Eur. J.Chem.2019, 9920–9929.Eur. J. 2019, 9920– 9929. Another subclass of rollover cyclometalation involves PˆN hemilabile ligands, such as phosphino pyridines. Goldberg and coworkers investigated the thermolysis behavior of FigureAnother 52. Synthesis subclass of the of dinuclear rollover hydrido cyclometalation complex 103 involves. Adapted P^N from hemilabile Chem. Eur. ligands, J. 2019, 9920– such two Pt(II) methyl-complexes [Pt(PˆN)Me ] where PˆN is (di-tert-butylphosphinito)pyridine 9929. 2 oras (di-phosphinotert-butylphosphino)-2-aminopyridine pyridines. Goldberg and coworkers104 (Figure investigated 53). the thermolysis behavior of two Pt(II) methyl-complexes [Pt(P^N)Me2] where P^N is (di-tert-butylphosphinito)pyr- idineAnother or (di-tert subclass-butylphosphino)-2-aminopyridine of rollover cyclometalation involves 104 (Figure P^N 53). hemilabile ligands, such as phosphino pyridines. Goldberg and coworkers investigated the thermolysis behavior of two Pt(II) methyl-complexes [Pt(P^N)Me2] where P^N is (di-tert-butylphosphinito)pyridine or (di-tert-butylphosphino)-2-aminopyridine 104 (Figure 53).

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Figure 53. Rollover with P^N hemilabile ligands.

Figure 53. FigureThe 53. Rollover authorsRollover with started,with PˆN P^N hemilabile as hemilabile usual ligands. for ligands. rollover Pt(II) processes, from the dimethyl adduct [Pt(P^N)MeThe authors2] (P^N started, = 104 as, usualX = O). for Heating rollover the Pt(II) complex processes, in frombenzene, the dimethyl in the presence adduct of pyr- The authors started, as usual for rollover Pt(II) processes, from the dimethyl adduct [Pt(PˆN)Meidine, activated2] (PˆN the = C(3)-H104, X =pyridine O). Heating bond the by complex means of in a benzene, rollover inpathway, the presence resulting of in the pyridine,[Pt(P^N)Mesynthesis activated of2 ]complex (P^N the = C(3)-H 104105,. XIn pyridine= contrastO). Heating bond to the by the meansphosphinito complex of a rolloverin complex,benzene, pathway, inthermolysis the resulting presence inof theof pyr- ad- idine, activated the C(3)-H pyridine bond by means of a rollover pathway, resulting in the theduct synthesis [Pt(P^N)Me of complex2] (P^N105 = .104 In contrast, X = NH) to resulted the phosphinito in a competition complex, thermolysis between intramolecular of the synthesis of complex 105. In contrast to the phosphinito complex, thermolysis of the ad- adductC–H activation [Pt(PˆN)Me via2] (PˆNrollover = 104 cyclometalation, X = NH) resulted and in a competitionintermolecular between benzene intramolecular C–H activation, ductC–H activation[Pt(P^N)Me via2 rollover] (P^N = cyclometalation 104, X = NH) resulted and intermolecular in a competition benzene between C–H activation, intramolecular with formation of a mixture of CH4 and CH3D [102]. with formation of a mixture of CH and CH3D [102]. C–H Finally,activation one via further rollover ligand cyclometalation4 potentially able and to intermolecular coordinate in differentbenzene C–Hways, activation, pyridine- withFinally, formation one further of a mixture ligand potentially of CH4 and able CH3D to coordinate [102]. in different ways, pyridineben- benzothiazole, reacted with PdCl2 in DMF under mild heating◦ (60 °C), activated the pyri- zothiazole,Finally, reacted one further with PdCl ligand2 in DMF potentially under mild able heating to coordinate (60 C), activatedin different the pyridineways, pyridine- C(3)–Hdine C(3)–H bond tobond afford to theafford rollover the rollover complex 106complex. Notably, 106 the. Notably, DMF solvent the DMF seems solvent to play seems to benzothiazole, reacted with PdCl2 in DMF under mild heating (60 °C), activated the pyri- aplay key a role key in role the rolloverin the rollover process, process, because becaus use of othere use solvents of other resulted solvents only resulted in classical only in clas- dine C(3)–H bond to afford the rollover complex 106. Notably, the DMF solvent seems to coordinationsical coordination (Figure (Figure 54)[103 ].54) [103]. play a key role in the rollover process, because use of other solvents resulted only in classical coordination (Figure 54) [103].

Figure 54.54.Rollover Rollover cylometalation cylometalation with with pyridinebenzothiazole. pyridinebenzothiazole. Adapted Adapted from Chemistry from Chemistry Select 2018 Select,

32018, 4133–4139., 3, 4133–4139. Figure 54. Rollover cylometalation with pyridinebenzothiazole. Adapted from Chemistry Select 4.2.2. Iridium and Rhodium Complexes 20184.2.2., 3 Iridium, 4133–4139. and Rhodium Complexes Iridium, as well as platinum, is able to produce the just discussed subclasses “carbene 4.2.2.CˆC rollover”Iridium, Iridium and asand well “pincer-rollover Rhodium as platinum, Complexes “complexes. is able to produce the just discussed subclasses “carbene C^CIn rollover” 2002, the and NHC-pyridine “pincer-rollover ligand “complexes.107, 1-[(2-(6-trimethylsilyl)pyridyl]-3-[(2,6-di-isopropyl)phenyl]imidazole-2-ylideneIridium,In 2002, theas well NHC-pyridine as platinum, (Figure ligand is able 55 107 to), showedproduce, 1-[(2-(6-trimethylsilyl)pyridyl]-3-[(2,6-di-iso- for the the just ﬁrst discussed time room-temperature subclasses “carbene C^C rollover” and “pincer-rollover “complexes. rolloverpropyl)phenyl]imidazole-2-ylidene C–H activation in a pyridine functionalized (Figure 55), with showed a heterocyclic for the carbene, first time by reactionroom-tempera- In 2002, the NHC-pyridine4 ligand 107, 1-[(2-(6-trimethylsilyl)pyridyl]-3-[(2,6-di-iso- withture therollover Ir(I) precursor C–H activation Ir(η -COD)Cl] in a pyridine2. This reaction functionalized allowed the with isolation a heterocyclic of the unusual carbene, by propyl)phenyl]imidazole-2-ylideneIr(III) CˆC rollover complex 108 in quantitativeη (Figure4 yield. 55), Theshowed reaction for with the thefirst analogous time room-tempera- Rh(I) reaction with 4the Ir(I) precursor Ir( -COD)Cl]2. This reaction allowed the isolation of the turecomplex rollover [Rh(h C–H-COD)Cl] activation2 gave in only a pyridine the classical functionalized Rh(I) cyclometalated with a heterocyclic carbene complex carbene, by unusual Ir(III)4 C^C rollover complex 108 in quantitative yield. The reaction with the anal- reaction[Rh(NˆC)(h with-COD)]+ the Ir(I) [104 precursor]. Ir(η4-COD)Cl]2. This reaction allowed the isolation of the ogous Rh(I) complex [Rh(h4-COD)Cl]2 gave only the classical Rh(I) cyclometalated car- unusual Ir(III) C^C rollover complex 108 in quantitative yield. The reaction with the anal- bene complex [Rh(N^C)(h4-COD)]+ [104]. ogous Rh(I) complex [Rh(h4-COD)Cl]2 gave only the classical Rh(I) cyclometalated carbene complex [Rh(N^C)(h4-COD)]+ [104].

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Figure 55. NHC-Ir(III) unusual C^C rollover complex 108. Reproduced (redrawn) from Ref. [104] withFigure permission 55.55. NHC-Ir(III) from The unusual Royal CˆCC^CSociety rolloverrollover of Chemistry. complexcomplex 108108.. ReproducedReproduced (redrawn)(redrawn) fromfrom Ref.Ref. [[104]104] withwith permissionpermission fromfrom TheThe RoyalRoyal SocietySociety ofof Chemistry.Chemistry. Years later, a second case of rollover cyclometalation promoted by [IrCp*Cl2]2 was

reportedYears with later,later, a abidentatea secondsecond casecasetriazolinylidene-pyrazole ofof rolloverrollover cyclometalation cyclometalation ligand. promotedpromoted The reactivityby by [IrCp*Cl [IrCp*Cl of the2 2]NHC-]22 waswas rolloverreported resulting withwith aa bidentatebidentate C^C chelated triazolinylidene-pyrazoletriazolinylidene-pyrazole complex was subsequently ligand. investigated The The reactivity in relation of the NHC-to in- sertionrollover reactions resulting [105]. C^C CˆC chelated chelated complex complex was was subsequently subsequently investigated investigated in inrelation relation to in- to insertionsertionThe reactions ligand reactions 2-[5-(pyridin-2-yl)-1 [105]. [105 ]. H-pyrrol-2-yl]pyridine, 109 (Figure 56), has a rich co- ordinationThe ligand ability, 2-[5-(pyridin-2-yl)-1 2-[5-(pyridin-2-yl)-1 being able to coordinateHH-pyrrol-2-yl]pyridine,-pyrrol-2-yl]pyridine, in different ways, 109beyond109 (Figure(Figure the 56),classical 56 has), has a N^N^N rich a rich co- tridentatecoordinationordination pincer ability, ability, mode. being being According able able to to coordinate coordinate to reacti inon in different differentconditions, ways, ways, N^N, beyond beyond N^N^C the the classical(rollover classical N^N^N NˆNˆNactiva- tiontridentatetridentate of external pincerpincer pyridine mode.mode. AccordingAccording ring), N^C to to reaction(rollove reactionr conditions, conditions,activation NˆN,of N^N, internal NˆNˆC N^N^C pyrrole) (rollover (rollover complexes activation activa- wereoftion external ofobtained external pyridine by pyridine reaction ring), ring),with NˆC [Ir(PPh (rolloverN^C (rollove3)3Cl]. activation Inr activationparticular, of internal of the internal Ir(III) pyrrole) compounds pyrrole) complexes complexes 110 were and 110 111 111obtainedwere were obtained byboth reaction formedby reaction with in refluxing [Ir(PPhwith [Ir(PPh3) 3toluene,Cl].3)3 InCl]. particular, following In particular, thetwo Ir(III) thedifferent Ir(III) compounds compoundsC–H bond rolloverand110 and activationwere111 were both formedbothpathways, formed in reﬂuxing in inthe refluxing pyrrole toluene, and toluene, following pyridine following two rings, different respectively.two different C–H bond This C–H rollover case bond represents activation rollover apathways,activation very rare pathways,incase the of pyrrole regioselective in the and pyrrole pyridine rollover and rings, pyridine activation respectively. rings, between respectively. This two case different represents This case rollover arepresents very path- rare wayscasea very of [106]. rare regioselective case of regioselective rollover activation rollover between activation two between different two rollover different pathways rollover [106 path-]. ways [106].

Figure 56.56. RolloverRollover cyclometalation cyclometalation at theat internalthe internal and externaland external rings of rings 2-[5-(pyridin-2-yl)-1 of 2-[5-(pyridin-2-yl)-1H-pyrrol-2-yl]pyridine.H-pyrrol-2-yl]pyridine. Adapted withAdaptedFigure permission 56. with Rollover permission from cyclometalationInorg. from Chem Inorg.. 2020 Chemat, 59 the,. 2,2020 internal 960–963., 59, 2, and Copyright960–963. external Copyright (2020) rings American of (2020) 2-[5-(pyridin-2-yl)-1 Am Chemicalerican Chemical Society.H-pyrrol-2-yl]pyridine. Society. Adapted with permission from Inorg. Chem. 2020, 59, 2, 960–963. Copyright (2020) American Chemical Society. ExamplesExamples of pseudo-rollover pseudo-rollover pathway, mediated both by Zr and Hf complexes, were shownshownExamples by neutral of pseudo-rollover Zr(IV) and Hf(IV)Hf(IV) pathway, alkyl/amidoalkyl/amido mediated complexes complexes both by Zrstabilized stabilized and Hf complexes, by a tridentate were N^N^NNˆNˆNshown by ligand,ligand, neutral whichwhich Zr(IV) containscontains and Hf(IV) aa “rolling”“rolling” alkyl/amido heterodentateheterodentate complexes benzoimidazolebenzoimidazole stabilized by fragment. a tridentate We onlyonlyN^N^N shortly ligand, mentionmention which thisthis contains casecase because because a “rolling” no no metal-carbon metal-carbon heterodentate bonds bonds benzoimidazole are are formed, formed, but fragment.but the the “rolling” “roll- We ing”benzoimidazoleonly benzoimidazoleshortly mention fragment fragment this gavecase gavebecause different different no NˆNˆN metal-carbon N^N^N tridentate tridentate bonds complexes are complexes formed, [107]. [107].but the “roll- Three further examples regarding polypyrazolyl ligands occurred with ruthenium, ing” Threebenzoimidazole further examples fragment regarding gave different polypyra N^N^Nzolyl tridentateligands occurred complexes with [107]. ruthenium, nickel, and iron complexes. nickel,Three and ironfurther complexes. examples regarding polypyrazolyl ligands occurred with ruthenium, The Ru(II) polypyrazolyl complex [(C(pz) )Ru(P-(OCH ) CEt)(CH CN)Me][BAr0 ], nickel,The and Ru(II) iron complexes.polypyrazolyl complex [(C(pz)4 4)Ru(P-(OCH2 23)3CEt)(CH33CN)Me][BAr′4], heated in a deuterated benzene solution in the presence of CH CN underwent rollover C–H ac- heated in a deuterated benzene solution in the presence of3 CH3CN underwent rollover The Ru(II) polypyrazolyl complex3 [(C(pz)4)Ru(P-(OCH2)3CEt)(CH3CN)Me][BAr0′4], tivation in one pyrazolyl ring to yield [(κ -(NˆCˆN)C(pz)4)Ru(P(OCH2)3CEt)(CH3CN)2][BAr 43] Cheated−H in activationa deuterated benzenein onesolution pyrazolylin the presence ring of CH 3CNto underwentyield rollover[(κ - and methane [108]. (N^C^N)C(pz)C−H activation4)Ru(P(OCH in2 )3CEt)(CHone 3CN)2][BArpyrazolyl′4] and methanering [108].to yield [(κ3- Intramolecular rollover C–H functionalization in a terdentate Ni azido complex (N^C^N)C(pz)Intramolecular4)Ru(P(OCH rollover2) 3CEt)(CHC−H functionalization3CN)2][BAr′4] and in amethane terdentate [108]. Ni azido complex Ni(NˆNˆN)(N3) occurred on one external pyrazolyl ring of the tridentate ligand, yielding Ni(N^N^N)(NIntramolecular3) occurred rollover on one C− Hexternal functionalization pyrazolyl ring in ofa theterdentate tridentate Ni ligand,azido yieldingcomplex an NˆNˆNˆC tetradentate rollover complex [109]. anNi(N^N^N)(N N^N^N^C tetradentate3) occurred onrollover one external complex pyrazolyl [109]. ring of the tridentate ligand, yielding Finally, a low-coordinate iron(II) complex with an NˆNˆN pincer ligand containing two hemilabilean N^N^N^C pyrazole tetradentate groups rollover underwent complex rollover [109]. C–H activation on one pyrazole affording an unusual pyrazolide-bridged iron(II) complex [110].

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Finally, a low-coordinate iron(II) complex with an N^N^N pincer ligand containing Molecules 2021, 26, 328 two hemilabile pyrazole groups underwent rollover C−H activation on one pyrazole34 of af- 58 fording an unusual pyrazolide-bridged iron(II) complex [110].

5. Organic Synthesis (Stochiometric Functionalization) 5. Organic Synthesis (Stochiometric Functionalization) The rollover reaction allows activation at C(3) position in 2,2’-bipyridines as well as The rollover reaction allows activation at C(3) position in 2,20-bipyridines as well as in analogous heteroaromatic ligands, a site which is typically hard to activate because in analogous heteroaromatic ligands, a site which is typically hard to activate because these chelated ligands are strongly bonded to the metalmetal andand C–HC–H bondsbonds activationactivation inin thisthis position requires partial ligandligand detachment.detachment. Once regiospecifically regiospeciﬁcally activated by means of rollover metalation, the C–H bond functionalization becomesbecomes accessible.accessible. In In this this chapter, chapter, we we report report stoichiometric stoichiometric functionalization functionaliza- tionreactions, reactions, leaving leaving catalytic catalytic processes processes to Section to chapter6. 6.

5.1. Palladium-Mediated Functionalization Taking advantage of rollover cyclometalation, inin 2010, Zucca and coworkers reported a ﬁrstfirst applicationapplication ofof rolloverrollover functionalizationfunctionalization ofof 2,22,2’-bipyridines.0-bipyridines. TheThe authorsauthors showedshowed that dinuclear palladium(II) ro rolloverllover derivatives [Pd(N^C)Cl] [Pd(NˆC)Cl]2 111 react in ethanolethanol withwith CO, under pressure at 60 ◦°C,C, affording the corresponding esters and acids, 112 and 113, respectively (Figure (Figure 57)57)[ [111].111]. As As key key steps steps of ofthe the process process were were proposed proposed insertion insertion of CO of intoCO intothe palladium–carbon the palladium–carbon bond bond(leading (leading an unstable an unstable six-membered six-membered acyl complex, acyl complex, subse- quentsubsequent nucleophilic nucleophilic attack attack of ethanol of ethanol on the on acylic the acylic carbonyl, carbonyl, and andfinal ﬁnal extrusion extrusion of the of theor- ganicorganic product product with with reductive reductive elimination elimination of palladium. of palladium. This This reaction reaction protocol protocol allowed allowed the synthesisthe synthesis of 2-(2-pyridin-2-yl)-6-alkyl-nicotinic of 2-(2-pyridin-2-yl)-6-alkyl-nicotinic acids acids or esters, or esters, derivatives derivatives which which are arera- therrather rare rare and and quite quite unreported unreported inin the the ca casese of of the the 6-substitu 6-substitutedted pyridine pyridine rings. rings.

Figure 57.57. SynthesisSynthesis of of 2-(2-pyridin-2-yl)-6-alkyl-nicotinic 2-(2-pyridin-2-yl)-6-alkyl-nicotinic esters esters by meansby means of rollover of rollover cyclometalation. cyclometalation.Reprinted Reprinted from J. Organomet. from J. Organomet. Chem., 2010 Chem, 695., ,2010 256–259., 695, Petretto,256–259. G.L.; Petretto, Zucca, G.L.; A.; StoccoroZucca, A.; S.; Stoccoro Cinellu, S.;M.A.; Cinellu, Minghetti, M.A.; G.Minghetti, Step by step G. Step Palladium by step mediated Palladium syntheses mediated of syntheses new 2-(pyridin-2-yl)-6-R-nicotinic of new 2-(pyridin-2-yl)- 6-R-nicotinic acids and esters. Copyright (2010), with permission from Elsevier. acids and esters. Copyright (2010), with permission from Elsevier.

5.2. Platinum-Mediate Platinum-Mediatedd Functionalization Starting from Pt(II) rollover precursors,precursors, aa sequencesequence ofof oxidativeoxidative addition-reductiveaddition-reductive elimination reactions can be useful for C–H bondbond functionalization of 2,22,2’-bipyridines.0-bipyridines. By Molecules 2021, 26, x FOR PEER REVIEW 35 of 59 reaction ofof Pt(II)Pt(II) rolloverrollover complexescomplexes [Pt(NˆC)Me(L)][Pt(N^C)Me(L)]114 114(L (L = = P P donor donor ligands) ligands) with with MeI, MeI, a aseries series of of analogous analogous Pt(IV) Pt(IV) complexes complexes are are readily readily accessible accessible (Figure (Figure 58 58).). This oxidative addition reaction has been studied in detail by several groups; as for classical cycloplatinated complexes, the reaction of rollover analogues with MeI proceeds thorough the classical SN2 oxidative addition mechanism. The reactions afford the analogous Pt(IV) complexes [Pt(NC)(L)(Me)2I]; even though several isomers can be formed, due to trans-phobia, only fac PtC3 isomers are expected to be fairly stable, so that, considering the presence of the cyclometalated ligand, only two isomers should realistically be formed, i) the “trans” isomer 115, which is expected to be the kinetic product, with the incoming ligands CH3 and I in mutual trans position, and the phosphane in “equatorial” position with respect to the bipyridine plane); ii) the “cis” isomer 116, i.e., the thermody- Figure 58. Oxidative addition reaction of MeI to Pt(II) rollover complexes.complexes. namic product, with the phosphane ligand in “axial” position. ThisKinetic oxidative and thermodynamic addition reaction factors has of been the studiedoxidative-addition in detail by reaction several groups;are regulated as for classicalby a mix cycloplatinatedof electronic and complexes, steric factors: the reactionelectron-richer of rollover Pt(II) analogues complexes with will MeI react proceeds faster, thoroughso that PMe the3 classicalcomplexes SN 2will oxidative be advantaged addition mechanism.towards PPh The3 analogues. reactions affordAt variance, the analo- the

gousPMe3 Pt(IV)ligand, complexes due to its [Pt(NC)(L)(Me) smaller cone angle,2I]; even will though remain several longer isomers in its position, can be formed, and the due ki- to trans-phobia, only fac PtC isomers are expected to be fairly stable, so that, considering netic isomer (PR3 in “equatorial3 positions) can be isolated and characterized, even by X- ray spectroscopy [112]. With bulkier phosphanes, such as PPh3 or PCy3, the isomerization to the thermodynamic product, i.e., the cis product, is faster. The influence of the cyclometalated ligand was studied by Rashidi and coworkers who reported the reactivity of the roll-over platinum(II) complexes [PtMe(bpy- H)(PPh2Me)] and [PtMe(bpy-H)(PPh3)], 114, with MeI, to give the corresponding rollover Pt(IV) complexes [PtMe2(bpy-H)(PR3)I]. Kinetic data suggested a classical SN2 mechanism with large negative DS‡ values. The PPh3 complex reacted slower with MeI than the PPh2Me one likely due to the stronger donor ability and the less steric hindrance of the PPh2Me ligand. Comparison with the classical cyclometalated complexes [PtMe(ppy- H)(L)], 117, (ppy-H = 2-phenylpyridinate, L = PPh3, PPh2Me) showed that rollover complexes reacted slower than phenylpyridine analog. This was attributed to the presence of the uncoordinated nitrogen atom which makes rollover coordinated 2,2’-bpy a slightly weaker donor than cyclometalated 2-phenylpyridine [113]. The same reaction was studied with the corresponding dinuclear double rollover complex 118, [Pt2(m-bpy-2H)Me2(PPh3)2]: Additionally, in this case, oxidative addition occurs, to give the dinuclear Pt(IV) complex 119 (Figure 59). The rate for the oxidative addition reaction was found to be almost 3–5 times slower in the second step (i.e., that on the second platinum center) as compared to the first one. This result is important, because it confirms transmission of electronic effects through the delocalized rollover bipy ligand. In comparison with the corresponding monomeric [Pt(bipy-H)Me(PPh3)] complex, in the dinuclear species 118, the rate for the oxidative addition reaction was found to be higher in step 1 and lower in step 2 [114].

Figure 59. Mono- and di-nuclear complexes 117–119.

The Pt(II) rollover complexes of these series have several nucleophilic centers, in particular, the uncoordinated nitrogen and the platinum(II). Hosseini and coworkers studied the reaction of three cyclometalated isomers [Pt(N^C)Me(PPh3)], 114, 120, and 121, with methyl iodide finding that only in the rollover complex, the stronger nucleophile is the platinum center, affording the Pt(IV) complex 116. In contrast, complexes 120 and 121 were predicted to react, by DFT calculations, with the nitrogen donor, to form N-methyl-

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the presence of the cyclometalated ligand, only two isomers should realistically be formed, i) the “trans” isomer 115, which is expected to be the kinetic product, with the incoming ligands CH3 and I in mutual trans position, and the phosphane in “equatorial” position Figure 58. Oxidative addition reaction of MeI to Pt(II) rollover complexes. with respect to the bipyridine plane); ii) the “cis” isomer 116, i.e., the thermodynamic product, with the phosphane ligand in “axial” position. Kinetic and thermodynamic factors of the oxidative-addition reaction are regulated Kinetic and thermodynamic factors of the oxidative-addition reaction are regulated by a mix of electronic and steric factors: electron-richer Pt(II) complexes will react faster, by a mix of electronic and steric factors: electron-richer Pt(II) complexes will react faster, so so that PMe3 complexes will be advantaged towards PPh3 analogues. At variance, the that PMe3 complexes will be advantaged towards PPh3 analogues. At variance, the PMe3 PMe3 ligand, due to its smaller cone angle, will remain longer in its position, and the ki- ligand, due to its smaller cone angle, will remain longer in its position, and the kinetic netic isomer (PR3 in “equatorial positions) can be isolated and characterized, even by X- isomer (PR3 in “equatorial positions) can be isolated and characterized, even by X-ray ray spectroscopy [112]. With bulkier phosphanes, such as PPh3 or PCy3, the isomerization spectroscopy [112]. With bulkier phosphanes, such as PPh3 or PCy3, the isomerization to theto the thermodynamic thermodynamic product, product, i.e., i.e., the thecis cisproduct, product, isfaster. is faster. The influenceinfluence ofof the the cyclometalated cyclometalated ligand ligand was was studied studied by Rashidiby Rashidi and coworkersand coworkers who who reported the reactivity of the roll-over platinum(II) complexes [PtMe(bpy- reported the reactivity of the roll-over platinum(II) complexes [PtMe(bpy-H)(PPh2Me)] H)(PPh2Me)] and [PtMe(bpy-H)(PPh3)], 114, with MeI, to give the corresponding rollover and [PtMe(bpy-H)(PPh3)], 114, with MeI, to give the corresponding rollover Pt(IV) com- Pt(IV) complexes [PtMe2(bpy-H)(PR3)I]. Kinetic data suggested a classical SN2 mechanism plexes [PtMe2(bpy-H)(PR3)I]. Kinetic data suggested a classical SN2 mechanism with large with large negative‡ DS‡ values. The PPh3 complex reacted slower with MeI than the negative DS values. The PPh3 complex reacted slower with MeI than the PPh2Me one PPh2Me one likely due to the stronger donor ability and the less steric hindrance of the likely due to the stronger donor ability and the less steric hindrance of the PPh2Me lig- and.PPh2Me Comparison ligand. Comparison with the classical with the cyclometalated classical cyclometalated complexes [PtMe(ppy-complexes H[PtMe(ppy-)(L)], 117, 3 2 (Hppy-)(L)],H 117= 2-phenylpyridinate, (ppy-H = 2-phenylpyridinate,, L = PPh3, PPh L2 =Me) PPh showed, PPh Me) that showed rollover complexesthat rollover reacted com- slowerplexes reacted than phenylpyridine slower than phenylpyridine analog. This was anal attributedog. This was to the attributed presence to of the the presence uncoordi- of natedthe uncoordinated nitrogen atom nitrogen whichmakes atom which rollover makes coordinated rollover 2,2 coordinated0-bpy a slightly 2,2’-bpy weaker a slightly donor thanweaker cyclometalated donor than cyclometalated 2-phenylpyridine 2-phenylpyridine [113]. [113]. The same reaction was studiedstudied withwith thethe correspondingcorresponding dinucleardinuclear doubledouble rolloverrollover complex 118,, [Pt [Pt22(m-bpy-2(m-bpy-2HH)Me)Me2(PPh2(PPh3)32]:)2 Additionally,]: Additionally, in inthis this case, case, oxidative oxidative addition addition oc- occurs,curs, to togive give the the dinuclear dinuclear Pt(IV) Pt(IV) complex complex 119 119(Figure(Figure 59). The59). rate The for rate the for oxidative the oxidative addi- additiontion reaction reaction was wasfound found to be to almost be almost 3–5 times 3–5 times slower slower in the in second the second step step (i.e., (i.e., that that on the on thesecond second platinum platinum center) center) as compared as compared to the to the first first one. one. This This result result is isimportant, important, because because it itconfirms confirms transmission transmission of of electronic electronic effects effects through through the the delocalized delocalized rollover rollover bipy bipy ligand. In comparison withwith thethe correspondingcorresponding monomericmonomeric [Pt(bipy-[Pt(bipy-HH)Me(PPh)Me(PPh33)] complex,complex, inin thethe dinuclear speciesspecies 118118,, thethe rate rate for for the the oxidative oxidative addition addition reaction reaction was was found found to to be be higher higher in stepin step 1 and 1 and lower lower in stepin step 2 [ 1142 [114].].

Figure 59. Mono- and di-nuclear complexes 117–119..

The Pt(II) Pt(II) rollover rollover complexes complexes of of these these series series have have several several nucleophilic nucleophilic centers, centers, in par- in particular,ticular, the uncoordinated the uncoordinated nitrogen nitrogen and the and platinum(II). the platinum(II). Hosseini Hosseini and coworkers and coworkers studied studiedthe reaction the reaction of three of cyclometalated three cyclometalated isomers isomers [Pt(N^C)Me(PPh [Pt(NˆC)Me(PPh3)], 1143)],, 120114, ,and120 ,121 and, with121, withmethyl methyl iodide iodide finding ﬁnding that that only only in the in the rollover rollover complex, complex, the the stronger stronger nucleophile nucleophile is the platinum center,center, affording affording the the Pt(IV) Pt(IV) complex complex116 116. In. contrast,In contrast, complexes complexes120 and 120121 andwere 121 predictedwere predicted to react, to react, by DFT by calculations,DFT calculations, with with the nitrogen the nitrogen donor, donor, to form to formN-methylated N-methyl- cyclometalated complexes 122 and 123 (Figure 60). The reasons for this different behavior in selectivity were found in the energy barrier needed for N-methylation (higher in the rollover complex) vs. oxidative-addition reactions [115].

2−

Figure 19

−

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ated cyclometalated complexes 122 and 123 (Figure 60). The reasons for this different be- Molecules 2021, 26, 328 Figure 48. 36 of 58 havior in selectivity were found in the energy barrier needed for N-methylation (higher

in the rollover complex) vs. oxidative-addition reactions [115].

−

Figure 60.Figure Figure 60. 60.Cyclometalated Cyclometalated complexes complexes derived derived from from bipyridine bipyridine isomers. isomers.

Shahsavari and coworkers studied the same oxidative reaction with thethe Pt(II)Pt(II) N-ON-O bipyridine-derived rollover complexes 124,, comparingcomparing threethree phosphanephosphane ligands:ligands: PPhPPh33, PPh2Me,Me, and and PPhMe PPhMe22 (Figure(Figure 61). 61). The The kinetic kinetic results results showed showed that that the the electronic electronic effects effects of ofthe the phosphanes phosphanes determine determine the the reaction reaction rates rates with, with, as as expected, expected, the the following trend: PPhMe2 >> PPh PPh2Me2Me > >PPh PPh3. As3. Aspreviously previously found, found, the trans the trans-cis isomerization-cis isomerization (kinetic (kinetic to ther- to thermodynamicmodynamic product) product) is mostly is mostly affected affected by steric by steric effects effects due dueto phosphane to phosphane ligands, ligands, so that so thatthe kinetic the kinetic trend trend is PPh is3 PPh > PPh3 >2Me PPh >2 MePPhMe > PPhMe2 [116].2 [116].

Figure 61.61. Pt(II) N-O bipyridine-derived rollover complexes 124124..

1 The same reaction,reaction, with deuterateddeuterated CDCD33I, was monitored byby NMR,NMR, evidencingevidencing aa scrambling between between the the incoming incoming CD CD3 3ligandligand and and the the preexisting preexisting CH CH3 ligand,3 ligand, which which ex- exchangechange their their mutual mutual positions. positions. In a successive paper, thethe samesame groupgroup studiedstudied thethe influenceinfluence of of the the rollover rollover cyclometa- cyclomet- latedalated ligand, ligand, comparing comparing the the cyclometalated cyclometalated N-O N-O bipyridyl bipyridyl ligand ligand with thewith classical the classical depro- tonateddeprotonated phenylpyridine phenylpyridine and benzo[h]quinoline and benzo[h]quinoline ligands ligands [117]. The [117]. study The showed study thatshowed the reactionthat the reaction rate in the rate oxidative in the oxidative addition addition of MeI is of significantly MeI is significantly slower with slower the with bipy- theN-oxide bipy- ligands,N-oxide showingligands, showing the effect the of theeffect N-O of groupthe N-O on group the Pt(II) on the reactivity. Pt(II) reactivity. The oxidativeoxidative additionaddition reaction reaction can can be be coupled coupled with with a successivea successive reductive reductive elimination elimina- steption step with with C-C couplingC-C coupling in order in order to obtain to obtain a functionalized a functionalized bipyridine. bipyridine. Starting Starting from from the Pt(II)the Pt(II) rollover rollover complexes complexes125 (Figure 125 (Figure 62), reaction 62), reaction with MeIwith gave MeI thegave corresponding the corresponding Pt(IV) complex 126. A subsequent reductive elimination promoted by abstraction of the iodide Pt(IV) complex 126. A subsequent reductive elimination promoted by abstraction of the ligand resulted in C(sp2)-C(sp3) bond formation to finally afford the 3-functionalized iodide ligand resulted in C(sp2)-C(sp3) bond formation to finally afford the 3-functional- 2,20-bipyridines 128: 3-methyl-2,20-bipyridine, 3,6-dimethyl-2,20-bipyridine, as well as ized 2,2’-bipyridines 128: 3-methyl-2,2’-bipyridine, 3,6-dimethyl-2,2’-bipyridine, as well 3-methyl-2-(20-pyridyl)-quinoline, which were isolated and characterized [118]. as 3-methyl-2-(2’-pyridyl)-quinoline, which were isolated and characterized [118]. The reductive elimination step involves a rare C(sp3)-C(sp2) coupling, in place of The reductive elimination step involves a rare C(sp3)-C(sp2) coupling, in place of the the more common C(sp3)-C(sp3) one (in this case, with ethane elimination), and whether more common C(sp3)-C(sp3) one (in this case, with ethane elimination), and whether this this reductive elimination takes place or not seems to be governed principally by steric reductive elimination takes place or not seems to be governed principally by steric factors, factors, as indicated by the behavior of PPh3, PMe3, and PCy3 complexes. Worth to as indicated by the behavior of PPh3, PMe3, and PCy3 complexes. Worth to note, the reac- note, the reaction occurs only in the presence of the uncoordinated nitrogen, typical of tion occurs only in the presence of the uncoordinated nitrogen, typical of rollover com- rollover complexes, because it takes advantage of a retro-rollover pathways, to give the plexes, because it takes advantage of a retro-rollover pathways, to give the intermediate intermediate NˆN chelated analogues 127. For this reason, the reaction is unique to rollover complexes;N^N chelated indeed, analogues the analogous 127. For this phenylpyridine reason, the reaction cyclometalated is unique complexes to rollover do complexes; not exhibit C–Cindeed, coupling the analogous when treated phenylpy withridine silver cyclometalated salts. complexes do not exhibit C–C coupling when treated with silver salts.

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Figure 62. Pt(II)-Pt(IV) mediatedFigure functionalization 62. Pt(II)-Pt(IV) mediated of 2,20-bipyridines functionalization by means of of 2,2’-bipyridines rollover C–H bond by means activation. of rollover Adapted C–H with permission from Chem.bond A Eur. activation. J. 2014, 20 Adapted, 5501–5510. with Copyright permission (2014) from JohnChemistry— Wiley &A Sons, Eur. Inc.J. 2014, 20, 5501–5510. Copy- right (2014) John Wiley & Sons, Inc. This route constitutes a new stoichiometric method for the activation and functional- izationThis of route C(3)-H constitutes position ina new bidentate stoichiometric heterocyclic method compounds. for the activation and functionalization of C(3)-H position in bidentate heterocyclic compounds. 5.3. Ruthenium-Mediated Functionalization 5.3. Ruthenium-MediatedA third case of rollover Functionalization metal-mediated C–H bond functionalization involves a series of rutheniumA third case complexes of rollover with metal-mediated cyclometalated C–H imines-based bond functionalization heterocycles [119 involves]. The reactiona series 6 ofof ruthenium [{RuCl(h -p complexes-cymene)}(m-Cl) with 2cyclometalated] with a series ofimines-based imines-based heterocycles heterocyclic [119]. ligands The (129 reac-) in tionthe presenceof [{RuCl(h of Cu(OAc)6-p-cymene)}(m-Cl)2 (Figure 632]) resultedwith a series in the of rollover imines-based cyclometalation heterocyclic due ligands to C–H (bond129) in activation the presence in the of C(3)Cu(OAc) position2 (Figure of the 63) ﬁve-membered resulted in the heterocyclicrollover cyclometalation ring (thiophene, due tobenzothiophene, C–H bond activation furan, in benzofuran, the C(3) position pyrrole, of andthe five-membered indole derivatives) heterocyclic affording ring rollover (thiophene,complexes benzothiophene,130. These complexes furan, benzofuran, unexpectedly pyrrole, react with and 3-hexyne indole derivatives) to give complexes affording131. rollover complexes 130. These complexes unexpectedly react with 3-hexyne to give （a） complexes 131.

（b）

Figure 63. (a) C-C coupling mediated by ruthenium rollover cyclometalation; (b) fused bis-heterocycles 132 and 133. AdaptedFigure with 63. permission from Chem. A Eur. J. 2012, 18, 15178–15189. Copyright (2012) John Wiley & Sons, Inc.

Successive reaction with CuCl2, promotes rearomatization of the ligand and release of the corresponding fused bis-heterocycles 132 and 133 (X = S, O, NMe) providing a novel Figure 63. (a) C-C coupling mediated by ruthenium rollover cyclometalation; (b) fused bis-hetero- synthetic method for the preparation of this family of compounds. cycles 132 and 133. Adapted with permission from Chem.—A Eur. J. 2012, 18, 15178–15189. Copy- Furthermore, the authors showed that it is also possible to obtain these organic right (2012) John Wiley & Sons, Inc. products in a one-pot sequential procedure allowing the synthesis of a series of new （a） derivatives.

（b）

Figure 78.

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Successive reaction with CuCl2, promotes rearomatization of the ligand and release of the corresponding fused bis-heterocycles 132 and 133 (X = S, O, NMe) providing a novel synthetic method for the preparation of this family of compounds. Molecules 2021, 26, 328 Furthermore, the authors showed that it is also possible to obtain these 38organic of 58 products in a one-pot sequential procedure allowing the synthesis of a series of new derivatives. Finally,Finally, in in may may be be mentioned mentioned a a particular particular case case of of C(3) C(3) bond bond functionalization functionalization in in 2,2’- 2,2bipyridine0-bipyridine which which does does not not involve involve transition transition metal metal coordination. coordination. TheThe reactionreaction of of penta- pentaphenylborolephenylborole with with 2,2’-bipyrid 2,20-bipyridineine forms forms anan adductadduct which, which, upon upon thermolysis, thermolysis, converts converts to tothe the orthoortho additionaddition product product 134134(Figure (Figure 64 64).).

Figure 64. 64.Reproduced Reproduced (redrawn) (redrawn) from from Ref. [ 120Ref.] with[120] permission with permission from The from Royal The Society Royal of Chemistry. Society of Chem- istry. An analogous reaction occurs with 2-phenylpyridine. Such reactivity is uncommon for main group elements and provides application to access boron compounds [120]. An analogous reaction occurs with 2-phenylpyridine. Such reactivity is uncommon 6.for Catalysis main group elements and provides application to access boron compounds [120]. Cyclometalated compounds have been widely used as catalysts [121,122]. As an example,6. Catalysis pincer complexes have demonstrated to be active in large series of catalytic reactions,Cyclometalated such as C–C bondcompounds coupling, have transfer been hydrogenation, widely used as alkane catalysts dehydrogenation, [121,122]. As an ex- andample, polymerization pincer complexes [123]. have demonstrated to be active in large series of catalytic reactions,Among such as the C–C various bond electronic coupling, and transfer steric hydrogenation, properties furnished alkane by dehydrogenation, cyclometalated and ligands, it is worth to remind that cyclometalation generates a formal carbanionic ligand, polymerization [123]. that enhances the electron density on the metal center. In addition to the classical case, rolloverAmong cyclometalation the various is able electronic to act as aand reversible steric pr process,operties allowing furnished to play by an cyclometalated uncommon lig- roleands, in it catalytic is worth reactions. to remind that cyclometalation generates a formal carbanionic ligand, that Thisenhances role can the assume electron two density different on aspects: the metal (i) rollover center. cyclometalated In addition complexes to the classical can case, berollover used as cyclometalation catalytic precursors, is able or to (ii) act the as rollover a reversible process process, can be one allowing step of to a catalyticplay an uncom- cycle.mon role In this in case,catalytic the catalytic reactions. precursor may be a non-organometallic species, and rollover complexesThis role are formed, can assume react, two and decoordinatedifferent aspects: in the i) course rollover of the cyclometalated catalytic cycle. complexes can 6.1.be used Rollover as Complexescatalytic asprecursors, Catalysts or ii) the rollover process can be one step of a catalytic cycle. In this case, the catalytic precursor may be a non-organometallic species, and rollo- To the best of our knowledge, the ﬁrst catalytic application of a rollover complex has beenver complexes reported in are 2009. formed, Bera and react, coworkers and decoordinate synthesized the in uncommonthe course Ir(III)of the complex catalytic135 cycle. (Figure 65) which incorporates a cyclometalated N-heterocyclic carbene and a rare “carbene- rollover”6.1. Rollover ligand. Complexes The complex, as Catalysts characterized by means of X-ray spectroscopy, proved to Molecules 2021, 26, x FOR PEER REVIEW 39 of 59 be catalyticallyTo the best active of our in theknowledge, hydrogen the transfer first catalytic reaction ofapplication aromatic and of a heteroaromatic rollover complex has ketonesbeen reported at room in temperature 2009. Bera with and highcoworker yieldss (Figure synthesized 65)[124 the]. uncommon Ir(III) complex 135 (Figure 65) which incorporates a cyclometalated N-heterocyclic carbene and a rare “carbene-rollover” ligand. The complex, characterized by means of X-ray spectroscopy, proved to be catalytically active in the hydrogen transfer reaction of aromatic and heteroaromatic ketones at room temperature with high yields (Figure 65) [124].

FigureFigure 65.65. CatalyticCatalytic activityactivity ofof thethe Ir-carbene-rolloverIr-carbene-rollover complexcomplex 135.135. AdaptedAdapted withwith permissionpermission fromfrom Inorg.Inorg. Chem.Chem. 2009,, 48,, 23,23, 11114–11122.11114–11122. Copyright (2009)(2009) AmericanAmerican Chemical Society.Society.

6.1.1. Platinum Catalyzed Reactions

A few years later, a new Pt(IV) rollover complex, [Pt(N^N^C)Cl3], 136 (Figure 66), was prepared by reaction of PtCl2 with a dimethyl quaterpyridine.

Figure 66. Pt(IV) rollover complex 136.

No experimental conditions for the synthesis were provided by the authors. The rollover complex 136, isolated and characterized by means, inter alia, of X-ray crystallography, showed to be a highly selective catalyst precursor in the hydrosilylation of styrene and terminal alkynes (Figure 67) [125].

Figure 67. Hydrosilylation of styrene.

6.1.2. Ruthenium Catalyzed Reactions As seen in Section 4.1.7, Niedner-Schatteburg, Thiel, and coworkers presented in 2013 the Ru(II) complex 68, able to convert into the corresponding rollover complex 69. Complex 68 was found to catalyze both the transfer hydrogenation of ketones and the reductive amination of aromatic aldehydes. The reactions proceed without presence of a base, an important feature which, for instance, prevents chiral compounds to undergo racemization. Indeed, the reported Ru(II)-rollover hydrogen transfer of arylalkyl ketones constitutes the first case of an air stable “phosphane-free” and “base free” hydrogen transfer catalysts [90]. The experimental and DFT data confirm that the key step of the self- activation of the catalyst is the C–H bond rollover activation in the pyrimidine ring. Four years later, a detailed mechanistic study on the process, extended to other related ligands, allowed the classification of the ligands according to their stereoelectronic properties. Additionally, in this case, rollover activation of the bidentate nitrogen ligand was proposed to be a key step of the process. DFT calculations, CID EIS-MS (CID = collision induced dissociation) and X-ray structural data helped the authors to conclude that a mix of electronic and steric factors were active in weakening critical metal-ligand bonds, favoring roll-over cyclometalation. In particular, the higher activity was shown with a tertiary amino substituent in the pyrimidine ring.

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Figure 65. Catalytic activity of the Ir-carbene-rollover complex 135. Adapted with permission from Inorg. Chem. 2009, 48, 23, 11114–11122. Copyright (2009) American Chemical Society. Molecules 2021, 26, 328 Figure 65. Catalytic activity of the Ir-carbene-rollover complex 135. Adapted39 with of 58 permission from Inorg. Chem. 2009, 48, 23, 11114–11122. Copyright (2009) American Chemical Society. 6.1.1. Platinum Catalyzed Reactions 6.1.1.A Platinum few years Catalyzed later, a newReactions Pt(IV) rollover complex, [Pt(N^N^C)Cl3], 136 (Figure 66), 6.1.1. Platinum Catalyzed Reactions was prepared by reaction of PtCl2 with a dimethyl quaterpyridine. 3 AA few few years years later, later, a new a Pt(IV) new rollover Pt(IV) complex, rollover [Pt(NˆNˆC)Cl complex,3 ],[Pt(N^N^C)Cl136 (Figure 66), was], 136 (Figure 66), preparedwas prepared by reaction by reaction of PtCl2 with of PtCl a dimethyl2 with quaterpyridine. a dimethyl quaterpyridine.

Figure 66. Pt(IV) rollover complex 136 . Figure 66. 66Pt(IV). Pt(IV) rollover rollover complex complex136. 136. No experimental conditions for the synthesis were provided by the authors. The roll- overNo complex experimental 136, conditionsisolated and for the characterized synthesis were by provided means, by inter the authors. alia, of The X-ray crystallog- rolloverNo complex experimental136, isolated conditions and characterized for the bysynthesis means, inter were alia, provided of X-ray crystallogra- by the authors. The roll- phy,overraphy, showed complex showed to be 136 to a highly be, isolated a highly selective and selective catalyst characterized precursor catalyst inprecursorby the means, hydrosilylation in inter the hydrosilylation alia, of styrene of X-ray crystallog- of styrene andraphy, terminal terminal showed alkynes alkynes to (Figurebe a (Figure highly 67)[125 67)selective]. [125]. catalyst precursor in the hydrosilylation of styrene and terminal alkynes (Figure 67) [125].

Figure 67. 67.Hydrosilylation Hydrosilylation of styrene. of styrene. 6.1.2.Figure Ruthenium 67. Hydrosilylation Catalyzed Reactions of styrene. 6.1.2.As Ruthenium seen in Section Catalyzed 4.1.7, Niedner-Schatteburg, Reactions Thiel, and coworkers presented in 2013 the6.1.2. Ru(II)As Ruthenium seen complex in Section68 Catalyzed, able to4.1.7, convert ReactionsNiedner-Schatteburg, into the corresponding Thiel, rollover and complex coworkers69. presented in 2013 the Ru(II)Complex complex68 was found 68, able to catalyze to convert both the into transfer the corresponding hydrogenation of ketonesrollover and complex the 69. reductiveAs seen amination in Section of aromatic 4.1.7, aldehydes. Niedner-Schatteburg, The reactions proceed Thiel, and without coworkers presence presented of in 2013 athe base, Ru(II)Complex an important complex 68 featurewas 68, foundable which, to to convert for catalyze instance, into both prevents the thecorresponding chiral transfer compounds hydrogenation rollover to undergo complex of ketones 69. and racemization.the reductiveComplex Indeed, amination68 was the reportedfound of aromatic to Ru(II)-rollover catalyze aldehydes. both hydrogen the The transfer transfer reactions of hydrogenation arylalkyl proceed ketones without of ketones presence and constitutestheof a reductivebase, an the important ﬁrst amination case of feature an of air aromatic stable which, “phosphane-free” aldehydes. for instance, The prevents and reactions “base chiral free” proceed hydrogencompounds without to presenceundergo transfer catalysts [90]. The experimental and DFT data conﬁrm that the key step of the ofracemization. a base, an important Indeed, the feature reported which, Ru(II)-rollo for instance,ver preventshydrogen chiral transfer compounds of arylalkyl to undergo ketones self-activationconstitutes the of the first catalyst case of is thean C–Hair stable bond rollover “phosphane-free” activation in the and pyrimidine “base free” ring. hydrogen trans- racemization.Four years later,Indeed, a detailed the reported mechanistic Ru(II)-rollo study onver the hydrogen process, extended transfer to of other arylalkyl ketones

relatedconstitutesfer catalysts ligands, the [90]. allowed firstThe case the experimental classiﬁcation of an air stable of and the “p ligands DFThosphane-free” accordingdata confirm to theirand that stereoelectronic“bas thee free” key hydrogenstep of the trans- self- properties.activationfer catalysts Additionally, of [90].the catalyst The in experimental this is case,the C–H rollover bondand activation DFT rollover data of the activation confirm bidentate that in nitrogen the the pyrimidine ligandkey step of ring. the self- was proposed to be a key step of the process. DFT calculations, CID EIS-MS (CID = collision activationFour yearsof the later,catalyst a detailed is the C–H mechanistic bond rollover study activation on the process, in the pyrimidineextended to ring. other re- inducedlated ligands, dissociation) allowed and X-ray the structuralclassification data helped of th thee ligands authors toaccording conclude that to atheir mix of stereoelectronic electronicFour and years steric later, factors a were detailed active inmechanistic weakening critical study metal-ligand on the process, bonds, favoringextended to other re- roll-overlatedproperties. ligands, cyclometalation. Additionally, allowed In the particular, in classification this thecase, higher rollove of activity thre activationligands was shown according withof the a tertiary bidentate to their amino stereoelectronicnitrogen ligand substituentproperties.was proposed in Additionally, the to pyrimidine be a key ring. in step this of case, the procerollovess.r DFTactivation calculations, of the bidentate CID EIS-MS nitrogen (CID =ligand colli- wassionA proposedinduced proposed dissociation) catalyticto be a cyclekey (Figurestep and ofX-ray 68 the), involving procestructuralss. hydrogen DFT data calculations, transferhelped reactions, the CIDauthors rollover EIS-MS to conclude (CID = colli- that anda mix retro-rollover of electronic reactions, and steric was supported factors bywere NMR active spectroscopy, in weakening kinetic studies, critical IR-MPD, metal-ligand bonds, ESI-MS,sion induced and DFT dissociation) calculations [18 and,71,72 X-ray,126]. structural data helped the authors to conclude that favoring roll-over cyclometalation. In particular, the higher activity was shown with a a mixDeveloping of electronic the potentialities and steric factors and applicability were active of the in Ru(II)-rollover weakening critical catalyst, metal-ligand Thiel bonds, andfavoringtertiary co-workers amino roll-over also substituent showed cyclometalation. that in complex the pyrimidine69 Inis highlyparticular, active ring. in the catalyzing higher the activity reductive was am- shown with a inationtertiary of amino aromatic substituent aldehydes with in iminesthe pyrimidine in 2-propanol, ring. which acts both as the hydrogen source and solvent [127].

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A proposed catalytic cycle (Figure 68), involving hydrogen transfer reactions, rollo- Molecules 2021, 26, 328 40 of 58 ver and retro-rollover reactions, was supported by NMR spectroscopy, kinetic studies, IR- MPD, ESI-MS, and DFT calculations [18,71,72,126].

Figure 68. Proposed mechanism mechanism for for catalytic catalytic transf transferer hydrogenation hydrogenation in in the the absence absence of of an an external external base. base. Reprinted Reprinted from from J. Organomet.J. Organomet. Chem Chem. 2018. 2018, 863, 863, 30–43., 30–43. Leist, Leist, M.; M.; Kerner, Kerner, C.; C.; Gh Ghoochany,oochany, L.T.; L.T.; Farsadpo Farsadpour,ur, S.; S.; Fizia, Fizia, A.; A.; Ne Neu,u, J.P.; J.P.; Schön, Schön, F.; F.; Sun, Y.; Oelkers,Oelkers, B.;B.; Lang,Lang, J.;J.; Menges,Menges, F.;F.; Niedner-Schatteburg, Niedner-Schatteburg, G.; G.; Salih, Salih, K.S.M.; K.S.M.; R. R. Thiel, Thiel, W.R. W.R. Roll-over Roll-over cyclometalation: cyclometalation: A A versatile tool to enhance the catalytic activity of transition metal complexes. Copyright (2018), with permission from versatile tool to enhance the catalytic activity of transition metal complexes. Copyright (2018), with permission from Elsevier. Elsevier. The hydrogenation of carbon monoxide to formate is catalyzed by another Ru(II) complex,Developing containing the potentialities a pincer NˆCˆN and di-pyridyl-imidazol-2-ylidene applicability of the Ru(II)-rollover ligand catalyst, [128]. AThiel key andstep co-workers of the catalytic also process showed was that proposed complex to69 be is ahighly rollover active switch in catalyzing of a pyridine the ligand reductive in a aminationbidentate former-pincerof aromatic aldehydes complex, towith afford imines an unusual in 2-propanol, C(carbene)ˆC(pyridyl) which acts both chelate. as the Thehy- drogenprocess source allows and hydride solvent exchange [127]. likely occurring via a dihydrogen complex according to the PerutzThe hydrogenation and Sabo-Etienne of carbon CAM mechanismmonoxide to (complex formate assisted is catalyzed metathesis) by another [129]. Ru(II) complex, containing a pincer N^C^N di-pyridyl-imidazol-2-ylidene ligand [128]. A key step6.1.3. of Palladium-Catalyzed the catalytic process Reactionswas proposed to be a rollover switch of a pyridine ligand in a bidentateThiel former-pincer and coworkers complex, synthesized to afford a series an unusual of Pd(II) C(carbene)^C(pyridyl) complexes with (2-aminopyrim- chelate. The processidinyl)phosphanes. allows hydride Among exchange the complexes,likely occurring besides via [Pd(NˆN)Cla dihydrogen2] complex adducts, according the rollover to thecomplexes Perutz and [Pd(PˆC)Cl Sabo-Etienne2], 137 CAM, were mechanis isolated andm (complex studied. assisted In these metathesis) complexes, [129]. the ligand, due to nitrogen protonation, acts as a formally neutral ligand and may be regarded as a 6.1.3.mesoionic Palladium-Catalyzed NHC ligand. The Reactions new complexes, adducts, and rollover cyclometalates were investigatedThiel and as coworkers catalysts insynthesized the Suzuki–Miyaura a series of Pd(II) coupling complexes reaction with of aryl (2-aminopyrim- halides with idinyl)phosphanes.phenylboronic acid atAmong room temperaturethe complexes, (Figure besides 69). [Pd(N^N)Cl The experimental2] adducts, data showedthe rollover that complexesslight changes [Pd(P^C)Cl at the amino2], 137 group, were of isolated the ligands and studied. result in In pronounced these complexes, differences the bothligand, in duethe stabilityto nitrogen and protonation, catalytic activity acts ofas thea formally corresponding neutral complexesligand and [ 130may]. be regarded as a mesoionicThe same NHC group, ligand. years The later, new reported complexes, the elevatedadducts, catalytic and rollover activities cyclometalates of the uncommon were investigatedrollover NHC as complex catalysts89 in(described the Suzuki–Miyaura in Section 4.2.1 coupling) in Suzuki–Miyaura reaction of aryl cross-coupling halides with phenylboronicreactions of arylboronic acid at room acids temperature with aryl chlorides (Figure 69). [100 The]. experimental data showed that

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slight changes at the amino group of the ligands result in pronounced differences both in the stability and catalytic activity of the corresponding complexes [130].

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Molecules 2021, 26, 328 41 of 58 slight changes at the amino group of the ligands result in pronounced differences both in the stability and catalytic activity of the corresponding complexes [130].

Figure 69. Pd(II) rollover complexes with (2-aminopyrimidinyl) phosphanes. Adapted from Eur. J. Inorg. Chem. 2011, 4603–4609.

The same group, years later, reported the elevated catalytic activities of the uncommon rollover NHC complex 89 (described in Section 4.2.1) in Suzuki–Miyaura cross-coupling reactions of arylboronic acids with aryl chlorides [100]. Figure 69.69.Pd(II) Pd(II) rollover rollover complexes complexes with with (2-aminopyrimidinyl) (2-aminopyrimidinyl) phosphanes. phosphanes. Adapted Adapted from Eur. from J. Eur. J. 6.2.Inorg. Rollover ChemChem. .2011 2011 Pathways, 4603–4609., 4603–4609. in Catalytic Cycles Several aspects of the rollover reaction, such as its reversibility, make it useful for 6.2. Rollover Pathways in Catalytic Cycles catalyticThe applications.same group, yearsA functionalization later, reported strategythe elevated for C–Ccatalytic coupling activities reactions of the mayuncom- in- Several aspects of the rollover reaction, such as its reversibility, make it useful for volvemon rollover coordination NHC complexof a bidentate 89 (described ligand, ro inllover Section C–H 4.2.1) bond in Suzuki–Miyauraactivation, metal-mediated cross-cou- catalytic applications. A functionalization strategy for C–C coupling reactions may involve functionalization,coordinationpling reactions of a of bidentate arylboronicand final ligand, decoordination acids rollover with C–H aryl bond of chlorides the activation, functionalized [100]. metal-mediated ligand. function- Other applica- tionsalization, may and involve ﬁnal decoordination a rollover-retro-rollover of the functionalized sequence ligand. with Other hydrogen applications transfer may reactions (Figureinvolve6.2. Rollover a70). rollover-retro-rollover Pathways in Catalytic sequence Cycles with hydrogen transfer reactions (Figure 70). Several aspects of the rollover reaction, such as its reversibility, make it useful for catalytic applications. A functionalization strategy for C–C coupling reactions may involve coordination of a bidentate ligand, rollover C–H bond activation, metal-mediated functionalization, and final decoordination of the functionalized ligand. Other applications may involve a rollover-retro-rollover sequence with hydrogen transfer reactions (Figure 70).

Figure 70.70.Rollover Rollover activation activation and and functionalization functionalization strategy. strategy. In the course of the last years, several synthetic catalytic protocols involving rollover In the course of the last years, several synthetic catalytic protocols involving rollover C–H activation and functionalization have been reported. We will present the results Caccording−H activation to the metaland functionalization used to catalyze the have reactions. been reported. We will present the results according to the metal used to catalyze the reactions. 6.2.1. Rhodium C–C Couplings 6.2.1.Figure Rhodium 70. Rollover activation and functionalization strategy. Being relatively rare, at least until a few years ago, rollover cyclometalation and/or acti- vationC–C CouplingsIn was the not course always of recognized. the last years, To the several best of synthetic our knowledge, catalytic theﬁrst protocols case of theinvolving rollover rollover catalyzed process was reported in 2009 by Miura et al., which showed that [RhCl(COD]2 Molecules 2021, 26, x FOR PEER REVIEWC−H Beingactivation relatively and functionalization rare, at least until have a few been years reported. ago,0 rollover We will cyclometalation present the42 of results59 and/or ac- catalyzes a consecutive double C–H bond activation in 2,2 -bipyridine affording the corre- activationspondingcording to 3,3 wasthe0-dialkenylated metalnot always used producttorecognized. catalyze by reaction the To reactions. the with best silylacetylene of our knowledge, (Figure 71 the)[131 first]. case of the rollover catalyzed process was reported in 2009 by Miura et al., which showed that [RhCl(COD]6.2.1. Rhodium2 catalyzes a consecutive double C–H bond activation in 2,2’-bipyridine affording the corresponding 3,3’-dialkenylated product by reaction with silylacetylene (Fig- ureC–C 71) Couplings [131]. Being relatively rare, at least until a few years ago, rollover cyclometalation and/or activation was not always recognized. To the best of our knowledge, the first case of the rollover catalyzed process was reported in 2009 by Miura et al., which showed that [RhCl(COD]2 catalyzes a consecutive double C–H bond activation in 2,2’-bipyridine affording the corresponding 3,3’-dialkenylated product by reaction with silylacetylene (Fig- Figureure 71) 71. [131]. Rh-catalyzed double C–H bond rollover functionalization in 2,22,2’-bipyridine.0-bipyridine.

In the following years, the Chang’s group group developed a catalytic catalytic method method for for the the func- func- tionalization of pyridine-based bi- and and tri-dentate tri-dentate ligands ligands by by means means of of a a rollover rollover pathway. pathway. The ﬁrstfirst paper of the series, in 2012 [[132],132], reportedreported thethe hydroarylationhydroarylation ofof alkenesalkenes andand alkynes with 2,22,2’-bipyridines0-bipyridines and 2,22,2’-biquinolines0-biquinolines promotedpromoted by Rh(III)-NHC (Nitrogen Heterocyclic carbene) catalysts. Two subsequent rollover cyclometalations give rise to double functionalization of the bidentate molecules (Figure 72). The rollover pathway is facilitated by the strong trans effect of the coordinated N-heterocyclic carbenes, which labilize the rhodium−pyridyl bond in trans position. The method enables a highly selective and efficient double functionalization of 2,2’-bipyridines and 2,2’-biquinolines.

Figure 72. Rollover hydroarylation of alkenes. Adapted with permission from J. Am. Chem. Soc. 2012, 134, 42, 17778−17788. Copyright (2012) American Chemical Society.

Application of the same protocol to tridentate N^N^N ligands, such as 2,2’:6’,2’’-terpyridine or related ligands, resulted in regioselective bis-alkylation of the terdentate ligands. The regioselectivity in the double C–H functionalization can be ascribed to a bis-rollover pathway preferring, as previously seen with Pt(II) [25], the central pyridine ring. The method allows the preparation, with high yields, of a series of functionalized tridentate compounds, with application to a wide range of tridentate heteroarenes and alkene reac- tants [133]. Rh(III)-NHC complexes (NHC = 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene) were also found to catalyze the selective rollover functionalization of 2-(2-thienyl)pyridine with a series of alkenes and internal alkynes. In course of the reaction, a rollover C– H bond activation converts the N^S chelated intermediate into a C^N rollover complex, by means of a proposed oxidative-addition process (Figure 73) [25].

Figure 73. Rh-catalyzed selective rollover functionalization of 2-(2-thienyl)pyridine.

As we will see hereinafter, the [RhCp*Cl2]2 catalyst has been used for a large series of rollover-catalyzed reaction. Recently, the regioselective C–H bond functionalization on tridentate 2,2’-bipyridine-6-carboxamides by means of a rollover pathway was reported [134].

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Figure 71. Rh-catalyzed double C–H bond rollover functionalization in 2,2’-bipyridine.

In the following years, the Chang’s group developed a catalytic method for the func- tionalizationFigure 71. Rh-catalyzed of pyridine-based double C–H bi- bond and tri-dentaterollover functionalization ligands by means in 2,2’-bipyridine. of a rollover pathway. The first paper of the series, in 2012 [132], reported the hydroarylation of alkenes and alkynesIn the with following 2,2’-bipyridines years, the and Chang’s 2,2’-biquinolines group developed promot a edcatalytic by Rh(III)-NHC method for (Nitrogen the func- Heterocyclictionalization carbene)of pyridine-based catalysts. bi- and tri-dentate ligands by means of a rollover pathway. TwoThe firstsubsequent paper of rollover the series, cyclometalations in 2012 [132], give reported rise to thedouble hydroarylation functionalization of alkenes of the and bi- Molecules 2021, 26, 328 dentatealkynes moleculeswith 2,2’-bipyridines (Figure 72). andThe rollover2,2’-biquinolines pathway promotis facilitateded by by Rh(III)-NHC the strong42 of 58 trans (Nitrogen effect ofHeterocyclic the coordinated carbene) N-heterocyclic catalysts. carbenes, which labilize the rhodium−pyridyl bond in transTwo subsequentposition. The rollover method cyclometalations enables a highly give selective rise to and double efficient functionalization double functionaliza- of the bi- tiondentate Twoof 2,2’-bipyridines molecules subsequent (Figure rollover and cyclometalations72). 2,2’-biquinolines. The rollover give pathway rise to double is facilitated functionalization by the strong of the trans effect trans bidentateof the coordinated molecules (Figure N-heterocyclic 72). The rollover carbenes, pathway which is facilitated labilize by the strongrhodium−effectpyridyl bond in of the coordinated N-heterocyclic carbenes, which labilize the rhodium–pyridyl bond in trans position. position. The The method method enables enables a highly a selectivehighly selective and efﬁcient and double efficient functionalization double functionaliza- oftion 2,2 of0-bipyridines 2,2’-bipyridines and 2,20 -biquinolines.and 2,2’-biquinolines.

Figure 72. Rollover hydroarylation of alkenes. Adapted with permission from J. Am. Chem. Soc. 2012, 134, 42, 17778−17788. Copyright (2012) American Chemical Society.

FigureApplication 72. 72.Rollover Rollover hydroarylation of hydroarylation the same of alkenes.protocol of alkene Adapted to s.tridentate Adapted with permission withN^N^N permission from ligands,J. Am. Chem.from such Soc.J. Am. as2012 2,2’:6’,2’’-ter-Chem., Soc. pyridine1342012, 42,, 134 17778, or42,− related17788.17778 Copyright−17788. ligands, Copyright (2012) resulted American (2012) in Chemicalregios Americelectivean Society. Chemical bis-alkylation Society. of the terdentate ligands. 0 0 ApplicationThe regioselectivity of the same in protocol the double to tridentate C–H functionalization NˆNˆN ligands, such can as be 2,2 ascribed:6 ,2”-ter- to a bis-roll- pyridineApplication or related ligands, of the resultedsame protocol in regioselective to tridentate bis-alkylation N^N^N of the ligands, terdentate such ligands. as 2,2’:6’,2’’-ter- overpyridineThe pathway regioselectivity or related preferring, ligands, in theas previously doubleresulted C–H in seenregios functionalization wielectiveth Pt(II) bis-alkylation [25], can bethe ascribed central of to pyridinethe a bis-terdentate ring. Thelig- methodrolloverands. pathway allows the preferring, preparation, as previously with seenhigh with yiel Pt(II)ds, of [25 a], series the central of functionalized pyridine ring. tridentate compounds,The methodThe regioselectivity allows with the application preparation, in the to double witha wide high C–H range yields, functionalization of of tridentate a series of functionalizedheteroarenes can be ascribed triden- and alkeneto a bis-roll- reac- tantstateover compounds, pathway[133]. preferring, with application as previously to a wide rangeseen ofwi tridentateth Pt(II) [25], heteroarenes the central and pyridine alkene ring. The reactantsmethodRh(III)-NHC [allows133]. the complexes preparation, (NHC with = high1,3-bis-(2,6 yields,-diisopropylphenyl)imidazol-2-ylidene) of a series of functionalized tridentate wereRh(III)-NHC also found complexes to catalyze (NHC the = selective 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene) rollover functionalization of 2-(2-thienyl)pyri- werecompounds, also found with to catalyze application the selective to a wide rollover range functionalization of tridentate of heteroarenes 2-(2-thienyl)pyridine and alkene reac- dinewithtants a with[133]. series a of series alkenes of andalkenes internal and alkynes. internal In course alkynes. of the In reaction, course aof rollover the reaction, C–H bond a rollover C– Hactivation bondRh(III)-NHC activation converts the complexesconverts NˆS chelated the (NHC intermediateN^S =chelated 1,3-bis-(2,6 into intermediate a CˆN-diisopropylphenyl)imidazol-2-ylidene) rollover into complex, a C^N by rollover means complex, byofwere ameans proposed also offound oxidative-additiona proposed to catalyze oxidative- processthe selectiveaddition (Figure rollover73 process)[25]. functionalization(Figure 73) [25]. of 2-(2-thienyl)pyridine with a series of alkenes and internal alkynes. In course of the reaction, a rollover C– H bond activation converts the N^S chelated intermediate into a C^N rollover complex, by means of a proposed oxidative-addition process (Figure 73) [25].

Figure 73. 73.Rh-catalyzed Rh-catalyzed selective selective rollover rollover functionalization functionalization of 2-(2-thienyl)pyridine. of 2-(2-thienyl)pyridine.

As we will see hereinafter, the [RhCp*Cl2]2 catalyst has been used for a large series of rollover-catalyzedAs we will see reaction. hereinafter, Recently, the the [RhCp*Cl regioselective2]2 catalyst C–H bond has functionalization been used for on a tri-large series of rollover-catalyzeddentateFigure 73. 2,2 0Rh-catalyzed-bipyridine-6-carboxamides reaction. selective Recently, rollover by means functionalizationthe regi of a rolloveroselective pathwayof 2-(2-thienyl)pyridine. C–H was bond reported functionalization [134 ]. on tridentateThe authors 2,2’-bipyridine-6-carboxamides showed that a series of 2,20-bipyridine-6-carboxamides by means of a rollover can bepathway selectively was reported [134].monoalkylatedAs we will at thesee C(3)hereinafter, position. Inthe the [RhCp*Cl proposed2 catalytic]2 catalyst cycle, has reported been used in Figure for a 74large, series of afterrollover-catalyzed coordination of reaction. the tridentate Recently, ligand andthe rolloverregioselective cyclometalation, C–H bond reaction functionalization with on sulfoxonium ylides gives carbene complexes. Subsequently, migratory insertion of the coordinatedtridentate 2,2’-bipyridine-6-carboxamides carbene into the Rh-C(3) bond is followed by means by of protonolysis, a rollover topathway give the was 3- reported alkylated[134]. products in high yields. This reaction protocol has a large applicability (the authors furnish 40 examples) and also showed an excellent tolerance to functional groups. In contrast to this “internal pyridine ring activation”, the Cheng group, working with the same ligands, presented a Pd(II)-catalyzed process in which the rollover process activates only the external pyridine ring (see later). Molecules 2021, 26, x FOR PEER REVIEW 43 of 59

The authors showed that a series of 2,2’-bipyridine-6-carboxamides can be selectively monoalkylated at the C(3) position. In the proposed catalytic cycle, reported in Figure 74, after coordination of the tridentate ligand and rollover cyclometalation, reaction with sulfoxonium ylides gives carbene complexes. Subsequently, migratory insertion of the coordinated carbene into the Rh-C(3) bond is followed by protonolysis, to give the 3-alkylated Molecules 2021, 26, 328 43 of 58 products in high yields. This reaction protocol has a large applicability (the authors furnish 40 examples) and also showed an excellent tolerance to functional groups.

Figure 74. Proposed catalytic cycle cycle for for the the alkylation alkylation of of 2,2’-bipyridine-6-carboxamides. 2,20-bipyridine-6-carboxamides. Adapted Adapted with permission from Org.Org. Lett. 2019,, 21,, 6366–6369.6366–6369. Copyright (2019) AmericanAmerican ChemicalChemical Society.Society.

CycloannulationIn contrast to Reactions this “internal pyridine ring activation”, the Cheng group, working with the sameFused ligands, polycyclic presented heteroarenes a Pd(II)-catalyzed constitute an process important in which scaffold the in rollover organic chemistry.process acti- In thisvates context, only the it isexternal well-known pyridine the ring rhodium(III)-catalyzed (see later). annulation of 2-phenylpyridines with alkynes: the reaction proceeds through successive C–C and C–N bond formations and isCycloannulation initiated by a C–H Reactions bond activation through cyclometalation [135–137]. In this framework, the [RhCp*ClFused polycyclic2]2 catalyst heteroarenes has been often constitute successfully an important used. A scaffold different in series organic of annulationchemistry. reactionsIn this context, involves it is a twofoldwell-known C–H the bond rhodium(III)-catalyzed cleavage and C–C bond annulation formation of and 2-phenylpyri- is initiated bydines means with of alkynes: rollover the C–H reaction bond activation proceeds and through metalation. successive This secondC−C and case C− appearsN bond to for- be attractivemations and because is initiated it enables by a the C–H assembly bond activation of different through polycyclic cyclometalation systems. The [135–137]. two possible In annulation reactions are reported in Figure 75. Path a represents single C–H bond cleavage Molecules 2021, 26, x FOR PEER REVIEWthis framework, the [RhCp*Cl2]2 catalyst has been often successfully used. A different44 of se- 59 andries C–Cof annulation and C–N bondreacti formations,ons involves whereas a twofold rollover C−H pathbond b cleavage represents and double C–C C–Hbond bond for- cleavagemation and and is twofold initiated C–C by bondmeans formation. of rollover C–H bond activation and metalation. This second case appears to be attractive because it enables the assembly of different polycyclic systems. The two possible annulation reactions are reported in Figure 75. Path a represents single C–H bond cleavage and C−C and C−N bond formations, whereas rollover path b represents double C–H bond cleavage and twofold C–C bond formation.

Figure 75.75.Possible Possible cycloannulation cycloannulation pathways pathways with with single single and double and double C–H bond C–H activations. bond activations. Adapted withAdapted permission with permission from Org. from Lett. 2015Org., Lett.17, 12, 2015 3130–3133., 17, 12, 3130–3133. Copyright Copyright (2015) American (2015) ChemicalAmerican Society. Chem- ical Society. Although the second pathway of 4 + 2 cycloannulation looks attractive, to the best of ourAlthough knowledge, the second it has not pathway been observed of 4 + 2 cycloa yet withnnulation 2-phenylpyridine. looks attractive, In contrast,to the best sev- of our knowledge, it has not been observed yet with 2-phenylpyridine. In contrast, several other heteroaromatic nitrogen ligands have been functionalized taking advantage of this reaction. Firstly, in 2011, Miura and coworkers reported the oxidative coupling of phenylazoles with internal alkynes, in the presence of [RhCp*Cl2]2 as catalyst and Cu(OAc)2 as oxidant. Several products were formed by means of double or even quadruple C–H bond activation. The reaction pathway was found to be highly dependent on the reaction conditions employed, and activation preferentially took place at the electron deficient sites in the aromatic rings. Among the various reaction pathways and the ample series of substrates and products, it should be mentioned for the first time a rollover annulation pathway, regarding 1-phenyl-pyrazoles, which implies a two-fold C–H bond activation to give the annulated compounds 138 (Figure 76) [138].

Figure 76. Cycloannulation reaction of 1-phenyl-pyrazoles alkynes. Adapted with permission from. J. Org. Chem. 2011, 76, 1, 13–24. Copyright (2011) American Chemical Society.

Modification of the heteroaromatic scaffold opens vast synthetic perspectives. Fol- lowing their studies, the same research group reported the rhodium-catalyzed dehydrogenative coupling of N-pyridylindoles with alkynes, in the presence of copper or silver salts. The reaction easily afforded indolo [1,2-a]-naphthyridine 139 derivatives following a rollover pathway [139]. According to reaction conditions (Cu or Ag salt as oxidant, choice of solvent, temperature, substrate), in addition to compound 139, also the C2- alkenylated product 140 was formed in different amounts. A plausible reaction mechanism, proposed by the authors, is reported in Figure 77.

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Figure 75. Possible cycloannulation pathways with single and double C–H bond activations. Adapted with permission from Org. Lett. 2015, 17, 12, 3130–3133. Copyright (2015) American Chem- ical Society.

Molecules 2021, 26, 328 Although the second pathway of 4 + 2 cycloannulation looks attractive, to44 the of 58best of our knowledge, it has not been observed yet with 2-phenylpyridine. In contrast, several other heteroaromatic nitrogen ligands have been functionalized taking advantage of this reaction.eral other heteroaromatic nitrogen ligands have been functionalized taking advantage of thisFirstly, reaction. in 2011, Miura and coworkers reported the oxidative coupling of phenylazoles withFirstly, internal in 2011, alkynes, Miura and in coworkersthe presence reported of [RhCp*Cl the oxidative2]2 as coupling catalyst of and phenylazoles Cu(OAc)2 as oxidant.with internal Several alkynes, products in the were presence formed of [RhCp*Clby means2] 2ofas double catalyst or and even Cu(OAc) quadruple2 as oxidant. C–H bond activation.Several products The reaction were formedpathway by was means found of double to be orhighly even quadrupledependent C–H on the bond reaction activa- con- tion. The reaction pathway was found to be highly dependent on the reaction conditions ditions employed, and activation preferentially took place at the electron deficient sites in employed, and activation preferentially took place at the electron deﬁcient sites in the thearomatic aromatic rings. rings. Among Among the variousthe various reaction reaction pathways pathways and the and ample the series ample of substrates series of sub- stratesand products,and products, it should it should be mentioned be mentioned for the fo ﬁrstr the time first a rollovertime a rollover annulation annulation pathway, pathway,regarding regarding 1-phenyl-pyrazoles, 1-phenyl-pyrazoles, which which implies implie a two-folds a two-fold C–H bond C–H activation bond activation to give the to give theannulated annulated compounds compounds138 138(Figure (Figure 76)[ 13876)]. [138].

Figure 76. CycloannulationFigure reaction 76. Cycloannulation of 1-phenyl-pyrazoles reaction alkynes. of 1-phenyl-pyr Adapted withazoles permission alkynes. from. AdaptedJ. Org. Chem. with2011 permission, 76, 1, 13–24. Copyright (2011)from. American J. Org. Chemical Chem. 2011, Society. 76, 1, 13–24. Copyright (2011) American Chemical Society. Modiﬁcation of the heteroaromatic scaffold opens vast synthetic perspectives. Follow- ingModification their studies, theof samethe heteroaromatic research group reported scaffold the opens rhodium-catalyzed vast synthetic dehydrogenative perspectives. Fol- lowingcoupling their of studies,N-pyridylindoles the same withresearch alkynes, group in the reported presence the of copperrhodium-catalyzed or silver salts. dehydro- The genativereaction coupling easily afforded of N-pyridylindoles indolo [1,2-a]-naphthyridine with alkynes,139 inderivatives the presence following of copper a rollover or silver salts.pathway The reaction [139]. According easily afforded to reaction indolo conditions [1,2-a]-naphthyridine (Cu or Ag salt as oxidant, 139 derivatives choice of solvent, following a rollovertemperature, pathway substrate), [139]. in According addition to to compound reaction 139conditions, also the C(Cu2-alkenylated or Ag salt product as oxidant, Molecules 2021, 26, x FOR PEER REVIEW 45 of 59 choice140 wasof solvent, formed in temperature, different amounts. substrate), A plausible in addition reaction mechanism,to compound proposed 139, also bythe the C2- alkenylatedauthors, is product reported in140 Figure was 77formed. in different amounts. A plausible reaction mechanism, proposed by the authors, is reported in Figure 77.

Figure 77. Plausible reactionFigure mechanisms 77. Plausible in the reaction Rh-catalyzed mechanisms dehydrogenative in the Rh-catalyzed coupling of dehydrogenativeN-pyridylindoles coupling with alkynes. of N- Adapted with permission frompyridylindolesOrg. Lett. 2015 with, 17 alkynes., 12, 3130–3133. Adapted Copyright with perm (2015)ission Americanfrom Org. ChemicalLett. 2015, Society. 17, 12, 3130–3133. Copyright (2015) American Chemical Society. This reaction protocol was successfully applied to a number of tetra-, penta-, and hexacyclicThis reactionN-containing protocol heteroaromatic was successfully compounds, applied showing to a numb to beer ofof ampletetra-, interest,penta-, and also hexacyclicbecause the N annulation-containing productsheteroaromatic exhibit compounds, intense ﬂuorescence showing in to thebe of solid ample state. interest, also because the annulation products exhibit intense fluorescence in the solid state. Other cases of oxidative rollover-annulation reactions catalyzed by Cp*Rh(III) complexes involve the oxidative annulation of 7-azaindoles and alkynes, taking advantage of the high reactivity of the 2-position in the pyrrole ring (Figure 78a) [140] and of 2-phenylimidazo[1,2-a]pyridines with alkynes, to give 5,6-disubstituted naphtho[1’,2’:4,5]imidazo[1,2-a]pyridines 141 and 142 (Figure 78b) [141].

Figure 78. Synthesis of 5,6-disubstituted naphtho[1’,2’:4,5]imidazo[1,2-a]pyridines. (a) 7-azaindoles and alkynes; (b) 2-phenylimidazo[1,2-a]pyridines with alkynes. Adapted with permission from. J. Org. Chem. 2015, 80, 7, 3471−3479. Copyright (2015) American Chemical Society.

The above-described method was also successfully applied to the annulation of pyridine-imidazolium substrates. Choudhury and coworkers reacted both normal [142] and abnormal [143] CHN imidazolium-based carbenes with internal alkynes, finding how stereoelectronic factors drive the process. Diﬀerent rollover C−H activation pathways were operative (NHC rotation vs pyridine rollover) depending on the properties of the organometallic intermediate, to give compounds 143 or 144 (Figure 79).

（a）

（b）

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Other cases of oxidative rollover-annulation reactions catalyzed by Cp*Rh(III) com- Figureplexes 63. involve the oxidative annulation of 7-azaindoles and alkynes, taking advantage of the high reactivity of the 2-position in the pyrrole ring (Figure 78a) [140] and of 2- phenylimidazo[1,2-a]pyridines with alkynes, to give 5,6-disubstituted naphtho[10,20:4,5]imidazo[1,2-a]pyridines 141 and 142 (Figure 78b) [141].

（a）

（b）

FigureFigure 78. 78. Synthesis of 5,6-disubstituted naphtho[10,20:4,5]imidazo[1,2-a]pyridines. (a) 7-azaindoles and alkynes; (b) 2-phenylimidazo[1,2-a]pyridines with alkynes. Adapted with permission from. J. Org. Chem. 2015, 80, 7, 3471–3479. Copyright (2015) American Chemical Society.

The above-described method was also successfully applied to the annulation of pyridine-imidazolium substrates. Choudhury and coworkers reacted both normal [142] and abnormal [143] CHN imidazolium-based carbenes with internal alkynes, ﬁnding how stereoelectronic factors drive the process. Different rollover C–H activation pathways Molecules 2021, 26, x FOR PEER REVIEW 46 of 59 were operative (NHC rotation vs pyridine rollover) depending on the properties of the organometallic intermediate, to give compounds 143 or 144 (Figure 79).

Figure 79. Bimodal rollover C–H bond activation: depending on steric (R1, R2) and electronic factors (R3, R4). Adapted with permissionpermission fromfromACS ACS Catal. Catal.2016 2016, 6, ,6 709–713, 709−713 (https://pubs.acs.org/doi/10.1021/acscatal.5b02540 (https://pubs.acs.org/doi/10.1021/acscatal.5b02540).). Copyright Copyright (2016) (2016) American Chemical Society. Further permissionspermissions relatedrelated toto thethe materialmaterial excerptedexcerpted shouldshould bebe directeddirected toto thethe ACS.ACS.

AnAn important novelty novelty of of these studies is the “controlled mechanistic dichotomy”, which allowed to switch the pathway of the functionalization functionalization reaction. The authors found thatthat the the reactions reactions were were selectively selectively driv drivenen toward toward rollover rollover or or non-rollover non-rollover C C–H−H function- function- alization routes on the basis of the steric and electronic properties of the rhodium(III) metallacyclic intermediates. In the presence of copper(II) acetate and non-polar solvent, the basic and coordinating acetate anion favor the rollover pathway leading to annulation products. In contrast, working in polar solvents with Cu(BF4)2 the influence of the BF4 anion (both weakly basic and coordinating) switches the reaction towards double alkyne insertion, affording C-N annulated cationic products [144]. Other cases of Cp*Rh(III)-catalyzed oxidative rollover-annulations with alkynes involve a series of pyridinones, to produce functionalized 4H-quinolizin-4-ones [145], and o-alkenyl anilides, from which unexpected naphthalene adducts were formed [146]. Recently, the cycloannulation Rh(III)Cp* catalytic protocol was extended to the functionalization of 2-(1H-pyrazol-1-yl)pyridine with internal alkynes. The reaction provided a switchable solvent-controlled C–H functionalization, affording alkenylated 2-(1H-pyrazol-1-yl)pyridine or indazole derivatives, with moderate to good yields. In both cases, only the pyrazolyl ring was involved in the C–H activation. Control experiments, conduced with “pre-rollover“ and “post-rollover” intermediates, suggested a rollover pathway for both cases [147]. The same strategy ([RhCp*Cl2]2 as catalyst, heating in the presence of AgOAc and a base) was adopted for 2,2’-bipyridine functionalization. Experimental and DFT data showed a considerable substituent effect: as often observed for substituted 2,2’-bipyridines, a substituent in position 6 plays an important role, weakening the nearby Rh–N bond and facilitating subsequent rollover C–H bond activation and functionalization [148]. Furthermore, the Rh-catalyzed oxidative annulation of imidazopyridines and indazoles was recently achieved using vinylene carbonate as a “vinylene transfer agent”. In the proposed reaction mechanism, a rollover C–H bond activation was a key step in the catalytic cycle [149]. The [RhCp*Cl2]2 complex was also reported to catalyze a divergent C–H bond activation and functionalization in aromatic picolinamide derivatives. Two sites for C–H activation are available, in pyridine and arene rings. Activation afforded isoquinoline derivatives or ortho-olefinated benzylamine (or phenethylamine) compounds, based on the

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alization routes on the basis of the steric and electronic properties of the rhodium(III) metallacyclic intermediates. In the presence of copper(II) acetate and non-polar solvent, the basic and coordinating acetate anion favor the rollover pathway leading to annulation products. In contrast, working in polar solvents with Cu(BF4)2 the inﬂuence of the BF4 anion (both weakly basic and coordinating) switches the reaction towards double alkyne insertion, affording C-N annulated cationic products [144]. Other cases of Cp*Rh(III)-catalyzed oxidative rollover-annulations with alkynes involve a series of pyridinones, to produce functionalized 4H-quinolizin-4-ones [145], and o-alkenyl anilides, from which unexpected naphthalene adducts were formed [146]. Recently, the cycloannulation Rh(III)Cp* catalytic protocol was extended to the functionalization of 2-(1H-pyrazol-1-yl)pyridine with internal alkynes. The reaction provided a switchable solvent-controlled C–H functionalization, affording alkenylated 2-(1H-pyrazol- 1-yl)pyridine or indazole derivatives, with moderate to good yields. In both cases, only the pyrazolyl ring was involved in the C–H activation. Control experiments, conduced with “pre-rollover“ and “post-rollover” intermediates, suggested a rollover pathway for both cases [147]. The same strategy ([RhCp*Cl2]2 as catalyst, heating in the presence of AgOAc and a base) was adopted for 2,20-bipyridine functionalization. Experimental and DFT data showed a considerable substituent effect: as often observed for substituted 2,20-bipyridines, a substituent in position 6 plays an important role, weakening the nearby Rh–N bond and facilitating subsequent rollover C–H bond activation and functionalization [148]. Furthermore, the Rh-catalyzed oxidative annulation of imidazopyridines and indazoles was recently achieved using vinylene carbonate as a “vinylene transfer agent”. In the proposed reaction mechanism, a rollover C–H bond activation was a key step in the Molecules 2021, 26, x FOR PEER REVIEW catalytic cycle [149]. 47 of 59

The [RhCp*Cl2]2 complex was also reported to catalyze a divergent C–H bond activation and functionalization in aromatic picolinamide derivatives. Two sites for C–H activation are available, in pyridine and arene rings. Activation afforded isoquinoline mechanism involved.derivatives This ordifferent ortho-olefinated reactivity benzylamine was achieved (or phenethylamine) switching the compounds,catalyst be- based on tween Rh(III) andthe Rh(I), mechanism which involved.results in Thisa mo differentdification reactivity of the mechanism was achieved of switchingthe process. the catalyst In addition, a seriesbetween of experimental Rh(III) and Rh(I), and which DFT resultsmechanistic in a modification studies helped of the mechanism to understand of the process. insights of the divergentIn addition, regiochemical a series of experimental outcome [150]. and DFT mechanistic studies helped to understand insights of the divergent regiochemical outcome [150]. Internal rotation of pyridine rings can assume various shapes: an internal rotation, Internal rotation of pyridine rings can assume various shapes: an internal rotation, without rolloverwithout C–H bond rollover activation C–H bond promotes activation intramolecular promotes intramolecular reaction of reaction 3-alkynyl of 3-alkynyl and and 3-alkenyl-2-arylpyridines, in the presence of [Cp*RhCl2]2 as catalyst and Cu(OAc)2 as cat- 3-alkenyl-2-arylpyridines, in the presence of [Cp*RhCl2]2 as catalyst and Cu(OAc)2 as catalytic additive. Thealytic reaction additive. allowed The reaction the allowedsynthesis the of synthesis new carbon of new skeleton carbon skeleton of 4-azafluo- of 4-azafluorenes renes 145 (Figure145 80)(Figure [151]. 80)[151].

Figure 80.FigureInternal 80. activationInternal activation reaction of reaction 3-alkynyl of arylpyridines. 3-alkynyl ar Adaptedylpyridines. with Adapted permission with from permissionOrg. Lett. 2012 from, 14 , 19, 5106–5109.Org. Copyright Lett. 2012 (2012), 14, 19, American 5106−5109. Chemical Copyright Society. (2012) American Chemical Society.

Two years later, the Rh(III)-catalyzed rollover method was extended to the synthesis Two years later, the Rh(III)-catalyzed rollover method was extended to the synthesis of a series of multicyclic heterocycles. The authors showed that intramolecular reaction of a series of multicyclicof 3-alkynyl-2-heteroarylpyridines heterocycles. The authors afforded showed tri- that and intramolecular tetracyclic nitrogen reaction heterocycles of 146 3-alkynyl-2-heteroarylpyridinesand 147 incorporating afforded also oxygen, tri- and sulfur, tetracyclic or nitrogen nitrogen (Figure heterocycles 81). Catalytic 146 amounts of and 147 incorporatingpivalate also or acetate oxygen, salts sulfur, were foundor nitrogen to facilitate (Figure the reaction.81). Catalytic Furthermore, amounts the of analogous pivalate or acetate salts were found to facilitate the reaction. Furthermore, the analogous reaction of 3-aryloyl-2-arylpyridines gave 7-substituted 4-azafluoren-9-ols. In order to prove the role of the pyridine nitrogen atom in the process, the authors showed that no reaction proceeded starting from nitrogen-free analogues, or positional isomers, not able to assist C–H bond cleavage and the subsequent rollover process [152].

Figure 81. Intramolecular alkyne insertion into 3-Alkynyl-2-heteroarylpyridines. Redrawn from Heteroatom Chemistry, 2014, 25, 5, 379–388, Ref. [152].

Internal rotation of a phenyl ring in a cyclometalated 2-phenylpyridine also occurs in the course of catalytic studies on the reaction with [RhCp*Cl2]2 and cyclopropenones [153].

Rotation of a Phenyl Ring

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mechanism involved. This different reactivity was achieved switching the catalyst between Rh(III) and Rh(I), which results in a modification of the mechanism of the process. In addition, a series of experimental and DFT mechanistic studies helped to understand insights of the divergent regiochemical outcome [150]. Internal rotation of pyridine rings can assume various shapes: an internal rotation, without rollover C–H bond activation promotes intramolecular reaction of 3-alkynyl and 3-alkenyl-2-arylpyridines, in the presence of [Cp*RhCl2]2 as catalyst and Cu(OAc)2 as catalytic additive. The reaction allowed the synthesis of new carbon skeleton of 4-azafluorenes 145 (Figure 80) [151].

Figure 80. Internal activation reaction of 3-alkynyl arylpyridines. Adapted with permission from Org. Lett. 2012, 14, 19, 5106−5109. Copyright (2012) American Chemical Society.

Two years later, the Rh(III)-catalyzed rollover method was extended to the synthesis of a series of multicyclic heterocycles. The authors showed that intramolecular reaction of Molecules 2021, 26, 328 47 of 58 3-alkynyl-2-heteroarylpyridines afforded tri- and tetracyclic nitrogen heterocycles 146 and 147 incorporating also oxygen, sulfur, or nitrogen (Figure 81). Catalytic amounts of pivalate or acetate salts were found to facilitate the reaction. Furthermore, the analogous reaction of 3-aryloyl-2-arylpyridines3-aryloyl-2-arylpyridines gave 7-substituted7-substituted 4-azaﬂuoren-9-ols.4-azafluoren-9-ols. In order toto prove the role of thethe pyridinepyridine nitrogen atom in thethe process,process, thethe authorsauthors showedshowed that nono reaction proceededproceeded startingstarting from from nitrogen-free nitrogen-free analogues, analogues, or or positional positional isomers, isomers, not not able able to toassist assist C–H C–H bond bond cleavage cleavage and and the th subsequente subsequent rollover rollover process process [152 [152].].

Figure 81.81. IntramolecularIntramolecular alkynealkyne insertioninsertion intointo 3-Alkynyl-2-heteroarylpyridines.3-Alkynyl-2-heteroarylpyridines. Redrawn from Heteroatom Chemistry,, 2014,, 25,25, 55,, 379–388,379–388, Ref.Ref. [[152].152].

Internal rotationrotation ofof aa phenyl phenyl ring ring in in a a cyclometalated cyclometalated 2-phenylpyridine 2-phenylpyridine also also occurs occurs in Molecules 2021, 26, x FOR PEER REVIEW 48 of 59 inthe the course course of catalyticof catalytic studies studies on the on reactionthe reaction with with [RhCp*Cl [RhCp*Cl2]2 and2]2 cyclopropenonesand cyclopropenones [153]. [153]. Rotation of a Phenyl Ring RotationSeveral of a papersPhenyl reportRing cases of “rollover”“rollover” activationactivation related toto phenylphenyl ringring rotationrotation instead of of heteroaromatic heteroaromatic ring ring rotation. rotation. This This generalization generalization of ofthe the rollover rollover concept concept is inis interesting,teresting, because because it enlarges it enlarges the thefield ﬁeld to an to ample an ample series series of internal of internal ring rotations, ring rotations, even eventhough though a “true” a “true”rollover rollover process process should shouldentail chelation entail chelation and internal and rotation internal of rotation heteroar- of heteroaromaticomatic rings. However, rings. However, an interesting an interesting example example of this of enlarged this enlarged interpretation interpretation is the is the([RhCp*Cl ([RhCp*Cl2]2 amination2]2 amination of arenes, of arenes, using using pyridine pyridine as a asdirecting a directing group. group. TheThe “rollover” “rollover” re- reaction,action, promoted promoted by by water, water, proceeds proceeds with with sele selectivityctivity on on a a wide wide range of substrates (both electron-deﬁcientelectron-deficient and electron-rich), affordingaffording bothboth mono-mono- andand di-aminated products 148148 and 149 (Figure(Figure 8282).). In this case, rotation ofof aa cyclometalatedcyclometalated phenyl ring is aa keykey stepstep ofof the process, and the pyridine nitrogen isis assumedassumed to retain its coordination to the rhodium center [[154].154].

Figure 82. OneOne example example of of rhodium-catalyzed rhodium-catalyzed mono mono and and diamination diamination of arenes. of arenes. Adapted Adapted with with per- permissionmission from from Org.Org. Lett. Lett. 20162016, 18,, 186, ,1386 6, 1386–1389.−1389. Copyright Copyright (2016) (2016) American American Chemical Chemical Society. Society.

A second case of “rollover” cyclometalation involving a phenyl ring rotation regards the selective bis-cyanation ofof arylimidazo[1,2-arylimidazo[1,2-α]pyridines byby meansmeans ofof doubledouble C–HC–H bondbond activation, once againagain with[RhCp*Clwith[RhCp*Cl22]2 as catalyst. The reacti reaction,on, which proceeds withwith wide functionalfunctional groupgroup tolerance,tolerance, enable enable the the synthesis synthesis of of various various cyanated cyanated imidazopy- imidaz- ridinesopyridines in high in high yields; yields; the reaction the reaction protocol prot wasocol alsowas explored also explored toward toward imidazo imidazo containing con- heterocyclestaining heterocycles [155]. [155].

6.2.2. Palladium At variance with rhodium, only a few cases of palladium-catalyzed reactions based on a rollover pathway were published in the course of the last years. In these cases, Pd(OAc)2 was used as catalyst. The first palladium-catalyzed process with an internal rotation of a pyridine-like ring regards the intramolecular aerobic oxidative C−H amination of 2-aryl-3-(arylamino)quinazolinones; the reaction afforded a series of fluorescent indazolo[3,2-b]quinazolinones derivatives, 151, in moderate to excellent yields (Figure 83). Mechanistic evidences suggested the cyclometalated palladium(II) dimer 150 as the key intermediate, which, after cyclometalation, underwent an internal rotation of the quinazolinone ring. The reaction should be classified as “pseudo-rollover” due to the absence of C–H bond activation in the heteroaromatic ring. It is worth to note that this approach to indazolo[3,2- b]quinazolinones has a “green” significance: in the course of the process, reaction with O2 as oxidant generates water as the only byproduct. Furthermore, the reaction products have potential utility as a new class of blue fluorophores for fluorescent materials [156].

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Several papers report cases of “rollover” activation related to phenyl ring rotation instead of heteroaromatic ring rotation. This generalization of the rollover concept is interesting, because it enlarges the field to an ample series of internal ring rotations, even though a “true” rollover process should entail chelation and internal rotation of heteroaromatic rings. However, an interesting example of this enlarged interpretation is the ([RhCp*Cl2]2 amination of arenes, using pyridine as a directing group. The “rollover” reaction, promoted by water, proceeds with selectivity on a wide range of substrates (both electron-deficient and electron-rich), affording both mono- and di-aminated products 148 and 149 (Figure 82). In this case, rotation of a cyclometalated phenyl ring is a key step of the process, and the pyridine nitrogen is assumed to retain its coordination to the rhodium center [154].

Figure 82. One example of rhodium-catalyzed mono and diamination of arenes. Adapted with permission from Org. Lett. 2016, 18, 6, 1386−1389. Copyright (2016) American Chemical Society.

A second case of “rollover” cyclometalation involving a phenyl ring rotation regards the selective bis-cyanation of arylimidazo[1,2-α]pyridines by means of double C–H bond activation, once again with[RhCp*Cl2]2 as catalyst. The reaction, which proceeds with wide functional group tolerance, enable the synthesis of various cyanated imidaz- Molecules 2021, 26, 328 48 of 58 opyridines in high yields; the reaction protocol was also explored toward imidazo containing heterocycles [155].

6.2.2. Palladium At variancevariance withwith rhodium, rhodium, only only a a few few cases cases of of palladium-catalyzed palladium-catalyzed reactions reactions based based on aon rollover a rollover pathway pathway were were published published in the coursein the ofcourse the last of years.the last In theseyears. cases, In these Pd(OAc) cases,2 wasPd(OAc) used2 aswas catalyst. used as catalyst. The firstThe firstpalladium-catalyzed palladium-catalyzed process process with with an internal an internal rotation rotation of a of pyridine-like a pyridine-like ring ring re- regardsgards the intramolecularintramolecular aerobic aerobic oxidative oxidative C–H aminationC−H amination of 2-aryl-3-(arylamino)quin- of 2-aryl-3-(aryla- azolinones;mino)quinazolinones; the reaction the afforded reaction afforded a series ofa se fluorescentries of fluorescent indazolo[3,2-b]quinazolinones indazolo[3,2-b]quinazo- derivatives,linones derivatives,151, in moderate151, in moderate to excellent to excellent yields yields (Figure (Figure 83). Mechanistic 83). Mechanistic evidences evidences sug- gestedsuggested the the cyclometalated cyclometalated palladium(II) palladium(II) dimer dimer150 150as theas the key key intermediate, intermediate, which, which, after af- cyclometalation,ter cyclometalation, underwent underwent an internalan internal rotation rotation of the of the quinazolinone quinazolinone ring. ring. The The reaction reac- shouldtion should be classified be classified as “pseudo-rollover” as “pseudo-rollover” due to due the to absence the absence of C–H of bond C–H activationbond activation in the heteroaromaticin the heteroaromatic ring. It is ring. worth It to is note worth that thisto note approach that tothis indazolo[3,2-b]quinazolinones approach to indazolo[3,2- hasb]quinazolinones a “green” significance: has a “green” in the significance: course of the in process, the course reaction of the with process, O2 as reaction oxidant with gener- O2 atesas oxidant water asgenerates the only byproduct.water as the Furthermore, only byproduct. the reaction Furthermore, products the have reaction potential products utility ashave a new potential class ofutility blue as fluorophores a new class for of fluorescentblue fluorophores materials for [fluorescent156]. materials [156].

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FigureFigure 83.83.Pseudo-rollover Pseudo-rollover intramolecular intramolecular oxidative oxidative C–H amination C−H amination of 2-aryl-3-(arylamino)quinazol- of 2-aryl-3-(arylamino)quinazolinones.inones. Adapted with permissionAdapted with from permissionOrg. Lett. 2014from, 16Org., 20, Lett 5418–5421.. 2014, 16 Copyright, 20, 5418–5421. (2014) Copyright American (2014)Chemical American Society. Chemical Society.

ChengCheng and coworkerscoworkers workedworked on on Pd(II) Pd(II) catalyzed catalyzed functionalization functionalization of 2,2of0 -bipyridine-2,2′-bipyridine-6-carboxamides6-carboxamides by means by means of rollover of rollover cyclometalation cyclometalation pathways. pathways. The researchers The researchers showed showedthat Pd(II) that acetate Pd(II) acetate catalyzes catalyzes the arylation the arylation of 2,2 0of-bipyridine-6-carboxamides 2,2′-bipyridine-6-carboxamides with with aryl aryliodides iodides in the in the presence presence of aof base. a base. Despite Despite the the presence presence in in the the substrate substrate ofof severalseveral sites availableavailable for for rollover rollover C–H C–H activation, activation, the the reaction reaction is regioselective, is regioselective, activating activating only only the theex- ternalexternal pyridine pyridine ring ring to togive give 152152 as asthe the final ﬁnal products products [157]. [157 The]. The authors, authors, on onthe the basis basis of theirof their experimental experimental results, results, propose propose a mechanism, a mechanism, reported reported in Figure in Figure 84, consisting 84, consisting in co- ordinationin coordination of the of tridentate the tridentate N^N^N NˆNˆN bipy bipyligand ligand (pre-rollover (pre-rollover complex, complex, isolated isolated and char- and acterized),characterized), rollover rollover cyclometalation cyclometalation only on only the onexternal the external pyridine pyridine ring, oxidative ring, oxidative addition ofaddition aryl iodide of aryl to iodideform a toPd(IV) form complex, a Pd(IV) complex,reductive reductiveelimination elimination of the arylated of the product. arylated Dueproduct. the great Due thearray great of substrates array of substrates studied, the studied, reaction the has reaction a broad has applicability. a broad applicability.

Figure 84. Proposed reactionFigure mechanism 84. Proposed (Pd(OAc)2, reaction Cs2CO3, mechanism mesitylene, (Pd(OAc)2, 160 ◦C, Cs2CO3, 24 h). Adapted mesitylene, with 160 permission °C, 24 h). from Adapted Org. Lett. 2018, 20, 4732–4735.with Copyright permission (2018) from American Org. Lett Chemical. 2018, 20, Society.4732–4735. Copyright (2018) American Chemical Society.

ItIt is is worth worth to to note that in a successive paper [135], [135], the functionalization of the same classclass of ligands, catalyzed by [RhCp*Cl2]]22,, acted acted regioselectively regioselectively on on the the internal C(3)-H bondbond (see (see Figure Figure 85). 85). This This constitutes constitutes a very a very interesting interesting case case of two of two different different rollover rollover regioselective functionalizations, where Pd(II) and Rh(III) catalysts activate in a selective way two different pyridine rings by means of distinctive rollover pathways.

Figure 85. Exclusive regioselective C–H bond functionalization of 2,2’-bipyridine-6-carboxamides. Adapted with permission from Org. Lett. 2019, 21, 6366–6369. Copyright (2019) American Chemi- cal Society.

As previously shown, an easy rollover metalation occurs with N-oxide-2,2’-bipyridine (see Chapter 4.1.2). Taking advantage of this, Tzschucke and coworkers studied the rollover C(3)−H halogenation of bipyridine N-oxides by reaction with N-chloro- or N- bromo-succinimide (NCS or NBS) using Pd(OAc)2 as catalytic precursor. C(3)-H pyridine functionalization gave 3-chloro- or 3-bromobipyridine N-oxides with high yields [158]. The authors found that the reaction is highly sensitive to steric hindrance in positions 4 and 6’. In the case of a 6’-substituted ligand coordination to palladium being hindered, and 3’-halogenation was observed. Deoxygenation with PCl3 or PBr3 allowed the obtainment of 3-halogenated bipyridines 153 (Figure 86).

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Figure 83. Pseudo-rollover intramolecular oxidative C−H amination of 2-aryl-3-(arylamino)quinazolinones. Adapted with permission from Org. Lett. 2014, 16, 20, 5418–5421. Copyright (2014) American Chemical Society.

Cheng and coworkers worked on Pd(II) catalyzed functionalization of 2,2′-bipyridine-6-carboxamides by means of rollover cyclometalation pathways. The researchers showed that Pd(II) acetate catalyzes the arylation of 2,2′-bipyridine-6-carboxamides with aryl iodides in the presence of a base. Despite the presence in the substrate of several sites available for rollover C–H activation, the reaction is regioselective, activating only the external pyridine ring to give 152 as the final products [157]. The authors, on the basis of their experimental results, propose a mechanism, reported in Figure 84, consisting in coordination of the tridentate N^N^N bipy ligand (pre-rollover complex, isolated and characterized), rollover cyclometalation only on the external pyridine ring, oxidative addition of aryl iodide to form a Pd(IV) complex, reductive elimination of the arylated product. Due the great array of substrates studied, the reaction has a broad applicability.

Figure 84. Proposed reaction mechanism (Pd(OAc)2, Cs2CO3, mesitylene, 160 °C, 24 h). Adapted with permission from Org. Lett. 2018, 20, 4732–4735. Copyright (2018) American Chemical Society. Molecules 2021, 26, 328 49 of 58 It is worth to note that in a successive paper [135], the functionalization of the same class of ligands, catalyzed by [RhCp*Cl2]2, acted regioselectively on the internal C(3)-H bond (see Figure 85). This constitutes a very interesting case of two different rollover re- regioselectivegioselective functional functionalizations,izations, where where Pd(II) Pd(II) and and Rh(III) Rh(III) catalysts catalysts activate activate in a selectiveselective wayway twotwo differentdifferent pyridinepyridine ringsrings byby meansmeans ofof distinctivedistinctive rolloverrollover pathways.pathways.

Figure 85. Exclusive regioselective C–H bond functionalization of of 2,2’-bipyridine-6-carboxamides. 2,20-bipyridine-6-carboxamides. AdaptedAdapted with permission from Org.Org. Lett. Lett. 20192019, ,2121, ,6366–6369. 6366–6369. Copyright Copyright (2019) (2019) American American Chemi- Chemi- cal Society.

As previouslypreviously shown,shown, an an easy easy rollover rollover metalation metalation occurs occurs with withN-oxide-2,2 N-oxide-2,2’-bipyri-0-bipyridine (seedine Section(see Chapter 4.1.2). 4.1.2). Taking Taking advantage advantage of this,of this, Tzschucke Tzschucke and and coworkers coworkers studied studied thethe rollover C(3)–HC(3)−H halogenation of bipyridine N-oxides by reaction with N-chloro- or N- bromo-succinimide (NCS(NCS oror NBS)NBS) usingusing Pd(OAc)2 asas catalytic precursor. C(3)-HC(3)-H pyridinepyridine functionalization gavegave 3-chloro- 3-chloro- or or 3-bromobipyridine 3-bromobipyridineN-oxides N-oxides with with high high yields yields [158 ].[158]. The authorsThe authors found found that thethat reactionthe reaction is highly is highly sensitive sensitive to steric to steric hindrance hindrance in positions in positions 4 and 4 0 0 Molecules 2021, 26, x FOR PEER REVIEW 6and. In 6’. the In casethe case of a 6of-substituted a 6’-substituted ligand ligand coordination coordination to palladium to palladium being50 of 59being hindered, hindered, and Molecules 2021, 26, x FOR PEER REVIEW0 50 of 59 3and-halogenation 3’-halogenation was observed.was observed. Deoxygenation Deoxygenation with with PCl3 PClor PBr3 or3 PBrallowed3 allowed the obtainment the obtain- ofment 3-halogenated of 3-halogenated bipyridines bipyridines153 (Figure 153 (Figure 86). 86).

Figure 86. Pd(II)FigureFigure rollover-catalyzed 86.86. Pd(II)Pd(II) rollover-catalyzedrollover-catalyzed synthesis of 3-halo synthesis synthesisgenated of of 3-halogenatedbipyridines. 3-halogenated Adapted bipyridines. bipyridines. with Adapted permis- Adapted with with permission permission from J. Org. Chem. 2017, 82, 11, 5616−5635. Copyright (2017) American Chemical Society. fromsion fromJ. Org. J. ChemOrg. Chem. 2017. ,201782, 11,, 82 5616–5635., 11, 5616−5635. Copyright Copyright (2017) (2017) American American Chemical Chemical Society. Society.

6.2.3. Rhenium6.2.3.6.2.3. Rhenium The ligand 2,7-dipyridinyl-1,8-naphthyridineTheThe ligandligand 2,7-dipyridinyl-1,8-naphthyridine2,7-dipyridinyl-1,8-naphthyridine can coordinate cancan in different coordinatecoordinate ways. inin differentdifferent This ways.ways. ThisThis ligand has twoligandligand external hashas pyridine twotwo externalexternal rings, pyridinepyridine making rings,itrings, able makingmakingto follow itit ablerolloverable toto followfollow pathways rolloverrollover and, pathwayspathways and,and, consequently, consequently,toconsequently, construct dinuclear toto constructconstruct complexe dinucleardinuclears. Under complexes.complexe certains. UnderUnderconditions, certaincertain a rhenium(I) conditions,conditions, aa rhenium(I)rhenium(I) mononuclear complexmononuclearmononuclear was complexobtainedcomplex was andwas obtained usedobtained for and the and usedsynthesis used for for the of the synthesis dinuclear synthesis of complexes. dinuclear of dinuclear complexes. complexes. The The first coordinationﬁrstThe coordinationfirst involves coordination a involves simple involves N^N a simple chelationa simple NˆN chelation N^Nof the chelation ligand, of the whereas of ligand, the ligand, whereasthe second whereas the second the second metal metal promotespromotesmetal a rollover promotes a cyclometalation. rollover a rollover cyclometalation. cyclometalation. In this way, In thishomo In way, this Re-Re, homoway, 154 homo Re-Re,, and Re-Re, heterodime-154, and154, heterodimetallicand heterodimetallic Re-Ir, Re-Pd,Re-Ir,tallic 155 Re-Ir, Re-Pd, and Re-Pd, 156155, andcomplexes 155156 and, complexes 156 were, complexes prepared were prepared wereand characterized prepared and characterized and (Figure characterized 87). (Figure (Figure 87). 87).

Figure 87. Homo and heterodimetallic Re complexes. Figure 87. HomoFigure and heterodimetallic 87. Homo and heterodimetallicRe complexes. Re complexes. Due to the capacity of rhenium carbonyl complex to catalyze the insertion of terminal Due to the capacityDue toof therhenium capacity carbonyl of rhenium comp carbonyllex to catalyze comp thelex insertionto catalyze of the terminal insertion of terminal acetylenes into b-keto esters, it was investigated the catalytic activities of these hetero- acetylenes intoacetylenes b-keto esters, into it b-keto was investigat esters, it edwas the investigat catalyticed activities the catalytic of these activities heterobi- of these heterobimetallic complexesmetallic on the complexes same reaction, on the samewithout reaction, any use without of organic any solvents.use of organic Among solvents. the Among the three dinuclearthree rollover dinuclear complexes, rollover only complexes, the dimetallic only Re-Rethe dimetallic complex Re-Re 154 showed complex to 154be showed to be active in the insertionactive in of the acetylenes insertion into of acetylenes β-keto esters, into under β-keto photoirradiation esters, under photoirradiation at 350 nm, at 350 nm, affording the correspondingaffording the corresponding5-oxo-2-hexenoates 5-oxo-2-hexenoates 157 with high 157yields with (Figure high yields88) [159]. (Figure 88) [159]. The heterodimetallicThe heterodimetallic complexes showed, complexes at variance, showed, scarce at variance, catalytic scarce activity. catalytic activity.

Figure 88. InsertionFigure of terminal 88. Insertion acetylenes of terminal into b-keto acetylenes esters into catalyzed b-keto byesters complex catalyzed 154. by complex 154.

7. Applications7. of Applications Rollover Complexes of Rollover Complexes Even though thisEven review though is dedicated this review to isaspects dedicated regarding to aspects C–H regarding bond activation C–H bond and activation and functionalization,functionalization, it may be of interest it may to be furnish of interest a brief to surveyfurnish ofa briefsome survey potential of some applica- potential applications of rollovertions cyclometalated of rollover cyclometalated complexes. This complexes. will highlight This thewill importance highlight the assumed importance assumed by the reactionby and the its reaction outcomes. and In its the outcomes. course of In the the last course years, of severalthe last potential years, several applica- potential applications were found.tions Synthetic were found. and catalyticSynthetic applications and catalytic have applications been reported have beenin Sections reported 5 in Sections 5 and 6, other fieldsand involve 6, other antitumor fields involve comp antitumorounds, chemosensors, compounds, chemosensors,and OLED emitters. and OLED emitters. Pt(II) rollover complexesPt(II) rollover with complexes 2,2’-bipyridines with 2,2’-bipyridines have been investigated have been for investigated their anti- for their antitumor properties.tumor In 2017,properties. Shahsavari In 2017, and Shahsavari coworkers and evaluated coworkers the biologicalevaluated activitythe biological of activity of a series of Pt(II)a rolloverseries of complexesPt(II) rollover with complexes 2,2’-bipyridine with 2,2’-bipyridineN-oxide and ancillary N-oxide phospho- and ancillary phospho-

Molecules 2021, 26, x FOR PEER REVIEW 50 of 59

Figure 86. Pd(II) rollover-catalyzed synthesis of 3-halogenated bipyridines. Adapted with permission from J. Org. Chem. 2017, 82, 11, 5616−5635. Copyright (2017) American Chemical Society.

6.2.3. Rhenium The ligand 2,7-dipyridinyl-1,8-naphthyridine can coordinate in different ways. This ligand has two external pyridine rings, making it able to follow rollover pathways and, consequently, to construct dinuclear complexes. Under certain conditions, a rhenium(I) mononuclear complex was obtained and used for the synthesis of dinuclear complexes. The first coordination involves a simple N^N chelation of the ligand, whereas the second metal promotes a rollover cyclometalation. In this way, homo Re-Re, 154, and heterodimetallic Re-Ir, Re-Pd, 155 and 156, complexes were prepared and characterized (Figure 87).

Figure 87. Homo and heterodimetallic Re complexes. Molecules 2021, 26, 328 50 of 58 Due to the capacity of rhenium carbonyl complex to catalyze the insertion of terminal acetylenes into b-keto esters, it was investigated the catalytic activities of these heterobimetallic complexes on the same reaction, without any use of organic solvents. Among the bimetallic complexes on the same reaction, without any use of organic solvents. Among thethree three dinuclear dinuclear rollover rollover complexes, complexes, onlyonly the the dimetallic dimetallic Re-Re Re-Re complex complex154 showed154 showed to to be beactive active in in the the insertion insertion ofof acetylenesacetylenes into intoβ-keto β-keto esters, esters, under under photoirradiation photoirradiation at 350 nm, at 350 nm, affording the the corresponding corresponding 5-oxo-2-hexenoates 5-oxo-2-hexenoates157 with 157 high with yields high (Figure yields 88)[ (Figure159]. The 88) [159]. heterodimetallicThe heterodimetallic complexes complexes showed, showed, at variance, at variance, scarce catalytic scarce activity. catalytic activity.

Figure 88. 88.Insertion Insertion of of terminal terminal acetylenes acetylenes into into b-keto b-keto esters esters catalyzed catalyzed by complex by complex154. 154. 7. Applications of Rollover Complexes 7. Applications of Rollover Complexes Even though this review is dedicated to aspects regarding C–H bond activation and functionalization,Even though it maythis review be of interest is dedicated to furnish to a aspects brief survey regarding of some C–H potential bond applica- activation and tionsfunctionalization, of rollover cyclometalated it may be of complexes. interest to This furnish will highlight a brief survey the importance of some assumed potential by applica- Molecules 2021, 26, x FOR PEER REVIEW 51 of 59 thetions reaction of rollover and its cyclometalated outcomes. In the complexes. course of the This last years, will highlight several potential the importance applications assumed wereby the found. reaction Synthetic and its and outcomes. catalytic applicationsIn the course have of the been last reported years, inseveral Sections potential5 and6, applica- othertions ﬁeldswere involvefound. antitumorSynthetic compounds, and catalytic chemosensors, applications and have OLED been emitters. reported in Sections 5 Pt(II) rollover complexes with 2,20-bipyridines have been investigated for their an- rusand ligands 6, other (Chapter fields involve 4.1.2) against antitumor a panel comp ofounds, standard chemosensors, cancer cell lines. and Two OLED of theemitters. com- titumor properties. In 2017, Shahsavari and coworkers evaluated the biological activity plexes showed a potent cytotoxic activity [53]. One year later, the same group extended of a seriesPt(II) of rollover Pt(II) rollover complexes complexes with 2,2’-bipyridines with 2,20-bipyridine haveN-oxide been investigated and ancillary for phos- their anti- the study to a series of cycloplatinated complexes (comprising rollover species) bearing phorustumor properties. ligands (Section In 2017, 4.1.2 )Shahsavari against a panel and ofcoworkers standard evaluated cancer cell lines.the biological Two of the activity of 1,10-bis(diphenylphosphino)ferrcomplexesa series of showed Pt(II) rollover a potent cytotoxiccomplexesocene activity with (dppf) [ 532,2’-bipyridine ].ligand. One year The later, authors N the-oxide same reported and group ancillary the extended biological phospho- evaluationthe study to of a seriesthe species of cycloplatinated as well as molecula complexesr docking (comprising studies. rollover The dppf-containing species) bearing roll- 1,10-bis(diphenylphosphino)ferroceneover complexes exhibited strong interactions (dppf) ligand. with DNA The authorsas well reportedas high cytotoxicity the biologi- and apoptosis-inducingcal evaluation of the activities species as to well human as molecular cancer cell docking lines [160]. studies. In the The same dppf-containing year, an in vitro studyrollover demonstrated complexes exhibited that one strongof the interactionsabove complexes with DNA has better as well cytotoxicity as high cytotoxicity effect against breastand apoptosis-inducing cancer cell lines than activities cis-platin to human [161]. cancer cell lines [160]. In the same year, an in vitroAgain,study in demonstrated the same year, that Babak, one of theHartinger, above complexes and coworkers has better presented cytotoxicity an important effect workagainst on breast the anticancer cancer cell activity lines than of acis series-platin of [mono-161]. and dinuclear Pt(II) rollover complexes withAgain, the simple in the 2,2-bipyridine same year, Babak, ligand. Hartinger, The complexes and coworkers demonstrated presented to an be important potent anti- worktumor on agents the anticancer both in vitro activity and of in a seriesvivo. ofSubstitution mono- and dinuclearof the neutral Pt(II) and rollover anionic complexes co-ligands withon the the Pt(k2NC-2,2’-bipyridyl) simple 2,2-bipyridine ligand. backbone The complexes allowed demonstratedto establish structure to be potent−activity antitumor relationships.agents The both authorsin vitro alsoand showedin vivo. that Substitution the proper ofties the of neutral the complexes and anionic can co-ligandsbe tuned in on order the Pt(k2NC-2,20-bipyridyl) backbone allowed to establish structure–activity relationships. to “target different cancer pathways” and “overcome the side effects associated with plat- The authors also showed that the properties of the complexes can be tuned in order to inum compounds in cancer chemotherapy” [162]. “target different cancer pathways” and “overcome the side effects associated with platinum compoundsAs previously in cancer commented, chemotherapy” in addition [162]. to Pt(II) derivatives, also Pt(IV) rollover com- plexesAs have previously shown commented, high cytotoxicity in addition towards to Pt(II) cancer derivatives, cells [46]. also Pt(IV) rollover com- plexesAn have interesting shown high potential cytotoxicity application towards of cancer Ir(III) cells rollover [46]. complexes was presented in 2015 Anby interestingLaskar and potential coworkers. application The ofcomplex Ir(III) rollover [Ir(PPh3)2(N^C)(Cl)(H], complexes was presented 158 (Figure in 2015 89), showedby Laskar properties and coworkers. that enable The complex it to be empl [Ir(PPh3)2(NˆC)(Cl)(H],oyed as a multi-responsive158 (Figure luminescent 89), showed mate- propertiesrial [163]. that enable it to be employed as a multi-responsive luminescent material [163].

Figure 89.89. Ir(III)Ir(III) complexescomplexes as as multi-responsive multi-responsive luminescent luminescent materials. materials.

The protonated form of the complex, 159, has been proven to be useful as a probe for solvents able to form H-bonds. The reversible protonation of complex 158 results in a dramatic change in emission color from bluish-green to yellowish-orange and vice versa after successive protonation and deprotonation reactions. This behavior allows the rollover complex 158 to act in several ways, as a phosphorescent acid sensor both in solution and in the solid state, and as a chemosensor for detecting acidic and basic organic vapors. In addition, the protonated form, [Ir(bipy-H)H+], which is generated after protonation of [Ir(bipy-H)], can be used as a “solvatochromic probe for oxygen containing solvents”. Further potential applications arise from the reversible protonation of the uncoordinated nitrogen in rollover helicenes 43 and 44, which allowed these organometallic compounds to act as “multifunctional switchable systems” [75]. Finally, the potential for the construction of emissive materials was also shown by the double rollover Pt(II) complex 39, described above [61], with potential applications as OLEDs.

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The protonated form of the complex, 159, has been proven to be useful as a probe for solvents able to form H-bonds. The reversible protonation of complex 158 results in a dramatic change in emission color from bluish-green to yellowish-orange and vice versa after successive protonation and deprotonation reactions. This behavior allows the rollover complex 158 to act in several ways, as a phosphorescent acid sensor both in solution and in the solid state, and as a chemosensor for detecting acidic and basic organic vapors. In addition, the protonated form, [Ir(bipy-H)H+], which is generated after protonation of [Ir(bipy-H)], can be used as a “solvatochromic probe for oxygen containing solvents”. Further potential applications arise from the reversible protonation of the uncoordinated nitrogen in rollover helicenes 43 and 44, which allowed these organometallic compounds to act as “multifunctional switchable systems” [75]. Finally, the potential for the construction of emissive materials was also shown by the double rollover Pt(II) complex 39, described above [61], with potential applications as OLEDs.

8. Conclusions and Perspectives Even after several years from its recognition as a distinct process, rollover cyclometalation can be still considered a relatively unexplored topic. Investigations in this field still constitute a small argument in chapters dedicated to cyclometalation, although their weight is constantly increasing. In our opinion, the field has only been marginally explored; as a matter of fact, only a few ligands have been investigated, among the plethora of heterocyclic ligands potentially available. In general, every bi- or polydentate ligand having two or more heterocyclic rings, sufficiently flexible to allow rotation of the rings and with C–H bonds “on the other side” (usually in symmetric position to one of the donor atoms), is potentially able to follow a rollover metalation. This allows a vast number of ligands to be studied, expanding the area to five- or six-membered heterocyclic rings, metallacycles of different size (e.g., five-, six-, or seven-membered rings) and different donors (N, S, P, C(sp2), C(sp3), normal or abnormal heterocyclic carbenes, etc.). As for all cyclometalated complexes, properties may be fine-tuned by modifications of the stereoelectronic properties of substituents on the heterocyclic rings, and by an adequate choice of coligands, oxidation state, and geometry. Whereas the chemistry of classical cyclometalated complexes has become a mature field of research, the same is far to be true for the rollover behavior. Mechanistic concepts have been only partly cleared up; whereas the C–H bond activation step is expected to follow related mechanisms in classical and non-classical cases, the factors which drive the conversion of stable chelated complexes into the corresponding rollover complexes is still an obscure matter: only for a few metals, methods for this conversion have been found. A great advancement of the field will be achieved by understanding this crucial step, which could allow the activation of a great number of chelated complexes and metals. On the whole rollover, cyclometalation constitutes a highly resourceful reaction with applications related to that of classical cases, enriched by the presence of the uncoordinated donor atom. This presence, which enables rollover ligands to be defined as “ligands with multiple personalities”, furnishes enhanced possibilities in biomedicine, for example, due to hydrogen-bonding interactions, in catalysis, due the reversibility of the rollover process (retro-rollover and hydrogen transfer reactions), in material chemistry (e.g., synthesis of homo and hetero-bimetallic systems with metals connected by a highly delocalized ligands), etc. Future developments in these fields are difficult to foresee, due to ample variability in metal, ligands, and substituents available, added to persisting obscurities in mechanistic aspects (both on the rollover process and on the behavior of rollover complexes). However, Molecules 2021, 26, 328 52 of 58

we can expect developments in catalyzed C-C coupling processes, hydrogen transfer reactions, photocatalysis, promoted by metals not yet investigated (e.g., Au, Pt, early transition metals, etc.). Advancements in biomedicine (e.g., antitumor and antimicrobial compounds) and material chemistry (sensors, switches, photosensitive devices, etc.) will be expected as well. However, it can be predicted that further progresses in the area will provide new unforeseen applications and developments contributing to enrich this promising ﬁeld of organometallic chemistry.

Author Contributions: Conceptualization, A.Z.; Funding acquisition, A.Z., M.I.P.; Writing—original draft, A.Z.; Writing—review & editing, A.Z., M.I.P. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Università degli Studi di Sassari, “Fondo di Ateneo per la ricerca 2019” and “Fondo di Ateneo per la ricerca 2020”. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Acknowledgments: A.Z. and M.I.P. gratefully acknowledge Università degli Studi di Sassari for financial support (“Fondo di Ateneo per la ricerca 2019”). Conflicts of Interest: The authors declare no conflict of interest.

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