As Nice as π: Aromatic Reactions Activated by π‐Coordination to Transition Metals

Abstract π‐Coordination of aromatic molecules to metals dramatically alters their reactivity. For example, coordinated carbons become more electrophilic and C−H bonds of coordinated rings become more acidic. For many years, this change in reactivity has been used to trigger reactions that would not take place for uncoordinated arenes, however, there has been a recent resurgence in use of this technique, in part due to the development of catalytic reactions in which π‐coordination is transient. In this Minireview, we describe the key reaction chemistry of arenes coordinated to a range of transition metals, including stereoselective reactions and industrially relevant syntheses. We also summarise outstanding examples of catalytic processes. Finally, we give perspectives on the future direction of the field, with respect to both reactions that are stoichiometric in activating metals and those employing catalytic metal.


Introduction
Since their discoveryi nt he 1950s by E. O. Fischer, [1] h 6 -arene complexes of transition metalsh ave been of widespread interest, due to the enhancement of the reactivity of the arene upon complexation ( Figure 1A). Coordination allows for the aromatic compound to undergo many reactions that are not possible fort he corresponding unbound arene. [2] For example, nucleophilic attack at the coordinated ring can result in substitution reactions of ring-bound substituents or,w here substitu-tion is not favoured, the formationo fh 5 -coordinated Meisenheimerc omplexes( Figure 1B), which are often stable and isolable. Other reactions at the bound aromatic include deprotonation, with subsequentr eaction with electrophiles, and oxidative addition. Following aromatic transformations, arenes are typicallyl iberated from the metal centre by photolytic or thermolytictechniques. [3] For some arenes and transition metals, pcomplexation is ar eversible process. Hence, it is possible to adapt the stoichiometrict ransformation of ac oordinated arene complex into ap rocess catalytic, with respectt ot he ML n core ( Figure 1C). This attractive prospectr equires balance between the reactivity of the coordinated arene and exchange of the coordinated arene product with the next equivalent of reactanta rene.
In this Minireview,w eh ighlight the key advances overt he last 20 years in both reactions of h 6 -coordinated aromatics and in reactions catalytic in the activating metal. We restricto ur scope to C 6 aromatics and omit examples that include chromium complexes as the activating group, which have been well reviewed elsewhere by Kündig [4] and by Matsuzaka and Takemoto. [5] We pay particular focus to suggestions for future development in the fielda nd pick out key publications that will pave the way for new reactions.

Reactivity of p-arene Transition Metal Complexes Chromium complexes
The early work on p-arene transition metal complexes focussedo n[ ( h 6 -C 6 H 6 )Cr(CO) 3 ]a nd related complexes to develop the fundamental understanding of the reactivity of the coordinated arene.T he reader is guided to several excellent reviews and book chapterso nt he early understanding of this complex and itsd erivatives. [4,6] More recently,t he reactivity of these Cr speciesh as furtherd eveloped into CÀHa ctivation and ar ange of Pd-catalysed couplingp rocesses, which have also been reviewed. [5,7] Molybdenum complexes In comparison with chromium, its Group 6c ongener molybdenum has received far less attention in the synthesis and application of p-arene complexes. This is likely due to the lower kinetic stabilityo ft he Mo complexes,limiting their practical utili- ty.Inarare example, the complex [(h 6 -C 6 H 6 )Mo(CO) 3 ]w as treated with an alkyllithium nucleophile, resultingi nf ormation of an anionic Meisenheimer complex 1 (Scheme 1). [8] Further treatment with allylb romide yieldedt he neutralc omplex [(h 3allyl)(h 5 -cyclohexadienyl)Mo(CO) 2 ]( 2), which, on treatment with CO gas, reductivelye liminated to give exclusivelyo ne diastereomero fa1,2-disubstituted cyclohexadiene 3.T his serves as an elegant example of the stereocontrol imparted by the metal complex, with the initial nucleophilic attack occurring at the top face of the arene. Further examples of Mo complex reactivity are rare, but sandwich complexes of the formula [Mo(h 6 -arene) 2 ]h ave been shown to be active towards lithiation, facilitating addition of electrophiles to the arene ring [9] and complexeso ft he form [Mo(h 6 -arene)(PR 3 ) 3 ]c an be used as precursors to other heteroleptic complexes,d ue to the lability of the coordinated arene. [10] Manganese complexes p-Arene complexes of the [Mn(CO) 3 ] + fragment are extremely stable and, due to the net positive charge, are highly susceptible to nucleophilic attack at the arene ring. Rose et al. used the [(h 6 -arene)Mn(CO) 3 ] + framework to develop enantioselective syntheses of substituted cyclohexenones from meta-halogenoanisoles. [11] Coordination of 1,3-disubstitued benzene to [Mn(CO) 3 ] + gives ap air of complexes (4)w ith planar chirality ( Figure 2A). Reaction with enantiopure (D)-(+ +)-camphor forms ap airo fd iastereomericM eisenheimer complexes (5), which can be separated by chromatography.T he chiral auxiliary can then be removed to yield enantiopure complexes 4a and 4b. As shown in Figure 2A,t hese complexes can be converted into enantiopure cyclohexenones in three steps. In ar elated study,t he naturalp roducts stemofurans were synthesised by nucleophilic substitution of hydrogen in [(h 6 -arene)Mn(CO) 3 ] + complexes with benzofuran. [12] In another study,t he scope of reactivity of Meisenheimer complexes structurally related to 6a towardsv arious nucleophilesw as established, [13] while earlier developmentsh ave been reviewed in detail by Rose and Rose-Munch. [14] Meisenheimer complexes of Mn I are often active towards organometallicc oupling reactions. For example, as eries of aryl chloride derived complexes (8), undergo Stille and Sonogashirac ouplings to give complexes 9 and 10,r espectively ( Figure 2B). [15] Am ore recent study reportedt he Suzuki-Miyaurac oupling of similarc hloro-substituted h 5 -coordinated Meisenheimer complexes (11), to give the arylated product 12. [16] Rearomatisation of the cyclohexadienyl ring in 12 can be achieved with the mild oxidant, trityl chloride. Further examples of Pd-catalysedr eactions [17]  to facilitatef ormation of ad inuclearM n-Fe complex, which has potential electronic applications [18] and the synthesis of organometallic phosphine complexes,u sed as ligandsi nc atalytic allylations. [19] Further owing to their high stability,M eisenheimer complexes of Mn I are active towards lithiation, enablingt he installation of electrophilic functional groupstot he ring before rearomatisation. [20] Optimisation of the lithiation/electrophilic quenching procedure led to am odel system ( Figure 2C), in which the reactions occur para to the sp 3 tetrahedral carbon of the Meisenheimer ring (13), forming complex 15 after electrophilicq uench, which could be purified to diastereomeric excesses of > 85 %. Reactivity of Meisenheimer Mn complexes has also been exploited to form keto- [21,22] and alcohol- [23] substitutedc yclohexadienyl complexes.I nanother study,G rignard reagents were reacted with keto-substituted cyclohexadienyl, giving the corresponding alcohols in excellent yields. [24] Acidification of these alcohols resulted in dehydration reactions, giving rise to as eries of novel h 5 -cyclohexadienyl complexes substituted by aC =Cdoubleb ond conjugated to the p-system of the ring.

Technetium and rhenium complexes
Unlike Mn complexes, there are very few examples of p-arene complexes of technetium,a lthough sandwich complexes of radioactive 99m Tc have been studied for their activity in biomimetic imaging. [25] In ar are example by Alberto and co-workers, an S N Ar hydroxylation of the complex [Tc(h 6 -C 6 H 5 Br)(h 6 -C 6 Me 6 )] + (16)w as described( Figure 3A), forming h 6 -phenol complex 17. [26] The corresponding rheniumc omplex (18)w as found to undergo ar ing contraction giving 21 ( Figure 3B) rather than the substitution product (20). [26] Based on positions of H/D exchange in ad euterium experiment, am echanism was proposed in which initially an ucleophilic attack of DO À takes place to form the Meisenheimer intermediate 19.H /D exchange was observed in this intermediate. An S N Ar reaction leadingt oc omplex 20 is promoted at lower deuteroxide concentrations, while ring contraction to form complex 21 is the favoured pathway when al arger excess of deuteroxide is present ( Figure 3B).
In am ore recents tudy,t he complex [Re(h 6 -C 6 H 6 ) 2 ] + (22)w as functionalised with ap olypyridyl group to form complex 23  ( Figure 3C). [27] Coordinationo fac atalytically active Co II centre to the polypyridyl moiety gave bimetallic complex 24,w hich was active in the photocatalytic reduction of protons to H 2 gas. The presence of the Re sandwich complex moiety in 24 adds structural support and flexibility to the catalytic species, as well as increasing aqueous solubility of the conjugate and adding resistance to deactivating redox processes.

Iron complexes
Arene p-complexes of iron were extensively researched in the late 20th Century.Some key studies conducted by Pearson and Shin included the synthesis of cyclic peptides via S N Ar [28] and the formation of aryl ethers from coordinated 1,3-dichlorobenzene. [29] Woodgatea lso used S N Ar reactions of coordinated arenes in the synthesis of dibenzo[b,e] [1,4]dioxind erivatives [30,31] and Astruc showedF e-mediated dendrimer synthesis, exploiting the increased acidity of benzylprotons on h 6 -coordination. [32] More recently,e xamples involving the use of iron have become scarce, due to the low stabilityo ft hese complexes relative to Ru analogues. One of few examples is an S N Ar-based approacht os ynthesise as eries of unsymmetrically substituted sterically congested benzophenones ( Figure 4A). [33] In ar are example of heterogeneous reactions involving parene metal complexes, ap iperazine nucleophile was tethered to as olid surface before S N Ar reactions with ar ange of [(h 6chloroarene)FeCp] + complexes were performed ( Figure 4B). The resultant immobilised Fe complexes were subjected to irradiationi nt he presence of phenanthrolinet ol iberate the Fearene bond and leave the aniline derivatives tethered to the solid surface. [34]

Ruthenium complexes
Since the turn of the century,r uthenium has gathered significant tractioni ni ts activation of arenes through p-coordination. This is due to the mild methods of complexation and demetallation,a sw ellash igh complex stability.

Rhodium and iridium complexes
Despite the prevalence of p-arene complexes of rhodium and iridium, [46,47] there are av ery limited number of examples where the arene is undergoing transformation while coordinated to the metal. One study demonstrates the reactivity of a series of [(h 6 -arylfluoride)RhCp'] 2 + complexes (Cp' = tetramethyl(ethyl) cyclopentadienyl). Reactivity of these complexesi s highly dependento nt he nature of the nucleophile (Figure 6A). [48] Hydroxide targets the polarised CÀFb ond, leading to an S N Ar process to give complex 43 ( Figure 6A), whilea lkyllithium nucleophiles attack one of the unsubstituted aryl C atoms. Reaction with LiCH(CO 2 Et) 2 results in Meisenheimer complex 44,w hich can undergo in situ oxidative rearomatisation to the free arene 45,u sing trifluoroacetic acid (TFA) and nitromethane. It is worth noting here that aR hc omplex 46 was also observed following the reaction, emphasising an ondestructive demetallation process.
As inglee xample of the reactivity of iridium p-arene complexes( Figure 6B)i nvolves oxidation of [Cp*Ir(h 6 -C 6 H 6 )] 2 + (47) to form the corresponding h 5 -cyclohexadienyl oxide (48). [49] Acidification with HBF 4 ·OEt 2 in acetonitrile liberates phenol and [Cp*Ir(NCMe) 3 ] 2 + with ay ield of 75 %. The overall process is catalytic in Ir,a s47 can be regenerated from the Ir product, however,t he conditions for oxidation and decomplexation are incompatible and the reactionr equires isolation at each stage.

Perspectives
The reactions described in this sectiond emonstrate the wide range of chemical reactivity of arenesb ound to varioust ransition metals and highlightst heir potentiala pplications in ak ey area of industriala nd pharmaceutical chemistry.C oordination to the metal centre enhances the reactivity of the arene and can controlt he regiochemistry of the reaction. Furthermore, as the metal coordinates to one face of the arene, complexation can allow for controlo fs tereochemistry and enantioselective syntheses. This stereocontrol has been used in the production of pharmaceutically relevant target compounds, such as the stemofurans. As ac hoice of activating metal, [Mn(CO) 3 ] + fragments are commonly used, due to their ease of synthesis and manipulation. However,t he oxidative techniques used to recover the arene product lead to loss of the Mn complexes. To develop more efficient andg reener processes it would be desirable to develop reactions in whicht he Mn I activating metal could be recovered or reused. As an alternative, Ru has become more prevalent as an activating metal,d ue to the ease of synthesis of their complexes and the ability to remove the reaction product by photolysis, regenerating the activating Ru fragment. For this method of aromatic activation to become competitive with other synthetic methodologies, effi-

Chemistry-A European Journal
Minireview doi.org/10.1002/chem.202004621 cient recovery of the metal is paramount.W hile homogeneous reactivity of activating p-arene complexes is common, only a single heterogeneous reaction is known.T here is great potential here for future studies on reactions in which the activating metal is tethered to as olid support to allow ease of purification and potentially access to flow systems for rapid and efficient synthesis. Ak ey limitation to the application of these reactions is the need for stoichiometric activating metal. This negative effectc an be offset by the ability to recycle the activating metal, however,amore desirable approachi st od evelop reactions that are catalytic in metal and proceed through transientf ormation of the active p-arene complex. In the next section, we give an overview of reactions that are catalytic in the activating metal.

Catalytic Transformations via Transient h6-Coordination
One challenge to developing catalytic reactions involving parene intermediates is finding conditions that are compatible with both the transformations tep and arene exchange. Ab alance between arene reactivitya nd arene exchange ability is necessary,b ecauseastronger arene-metal interaction typically leads to ag reater reactivity of the ring, but disfavours arene exchange. The factors that affect arene exchange have been reviewed elsewhere. [3,6] Despite the difficulty in achieving this balance,t here are several cases published, mostly in the past 10 years, where the arene transformation is catalytic in the activating metal.

Reactions catalytic in ruthenium
The most commonc lass of catalytic reactions proceeding via h 6 -arene intermediates are S N Ar reactions with catalytic Ru. [50] The first example came from Shibata on the amination of unactivatedf luoroarenes, proceeding via Ru II intermediates 49 a and 49 b (Table 1, Entry 1). [51] Reaction conditions involved aR u cyclooctadiene catalyst, phosphine DPPPentl igand and additives TfOH and Et 3 SiH. Recently,M ueller and Schley carried out ad etailed mechanistics tudy on the reaction between fluoro- Table 1. CatalyticS N Ar proceedingt hrough p-areneintermediates.
In 2020, Shi and co-workersp resented as imilarp rocedure for ruthenium catalysed S N Ar coupling of fluoroarenes with amines (Table 1, Entry 4), proceeding via intermediates 52 a and 52 b. [54] By using ah emilabile phosphine ligand,abalance between reactivity and arene exchange was achieved and the reactionp roceeded to excellent yields for ar ange of aryl fluorides and amines under mild reaction conditions. Key to this successw as the proposed catalytic intermediates, 52 a and 52 b,w hich incorporate two phosphine ligands: one bidentate and the other monodentate. Rapid S N Ar is followed by arene exchange, which is accelerated throught ransient coordination of the second hemilabile phosphine ligand ( Figure 7A). As evidence for this process, ar elatedp hosphine ligand withoutt he second coordinating group showed no release of the reaction product from complex 55 ( Figure 7B).
The previouse xamples of catalytic S N Ar are limited to fluoroarenes, with no reactivity shown for aryl chlorides or bromides.S uccessful reaction procedures using chloroarenes have been developedm ore recently.T he first example is the catalytic S N Ar of aryl chlorides shown by our laboratory in 2015 (Table 1E ntry 5). [55] Using 10 mol %o ft he precatalyst[ CpRu(h 6p-cymene)][PF 6 ], p-chlorotoluene wascoupled with morpholine in 90 %y ield. From spectroscopic data, we inferred complex 53 a as the activei ntermediate. In ar elated study,G rushin achieved ac atalytic fluorination of aryl chlorides via S N Ar (Table 1, Entry 6). [56] Using the pre-catalyst [Cp*Ru(h 6 -naphthalene)][BF 4 ] and CsF as the nucleophilic fluorides ource,t he reaction proceeded at 140 8Ci nd ry DMF,v ia intermediates 54 a and 54 b, with ac atalytic turnover number (TON) of 4.3a fter 24 hours. Compared with the previouse xample, this reactionw orks at a lower temperature, which is potentially due to the more electron-rich Cp* facilitating arene exchange better than Cp. When the reaction was performed in neat chlorobenzenea t1 80 8C, an improved TON of 8.5 was observed.
Catalytic S N Ar reactions are all activated by the increase in electrophilicity of the Ru-bound aromatic ring. This enhancement of reactivity also extends beyondt he coordinatedr ing to more distal positions. The earlieste xample of catalytic activation via this route was the Ru-catalyseda nti-Markovnikov hydroamination of styrene derivatives with secondary amines, re-ported by Hartwig et al. in 2004 (Figure7D). [57] In this study, the hydroaminationw as facilitated by the stabilisation of the Ru-bound intermediate that places negative chargei nt he apositiono fc oordinated styrene. Conjugation with the coordinated arene provides this stabilisation and the resultant optimised yields were up to 95 %. In ar elated study,e nantioselective addition to a-methylstyrene was achieved using ac hiral bisphosphine ligand. [58] Chirality in the ligand rendersc omplexes 56 a and 56 b diastereomeric. After nucleophilic attack, protonation occurs on the less hinderedf ace away from the Ru, hence ap reference for one diastereomeru ltimately leads to enantioselectivity in the final uncoordinated product.
Af inal example of catalysis via transientR up-arene complexese xploits the increased acidity of benzylic protons of coordinated arenes. [59] The production of trans-stilbene derivatives was shown via ad ehydrativecondensation of benzylic CÀ Hb onds with aromatic aldehydes ( Figure 8A). [60] Using 10 mol %o ft he catalyst[ Cp*Ru(h 6 -toluene)][HNTs],t oluene was coupled with as eries of aromatica ldehydes at 150 8Ci n yields of up to 95 %. The key intermediate in the mechanism is 57b,i nw hich deprotonation at the benzylic position of toluene is stabilised by Ru coordination.A ss hown in Figure 8A, this intermediate goes on to react with benzaldehyde, which itself is activated to an imine by the Ru complex counterion [HNTs] À .T he organocatalytic behaviour of this ion wasf ound to be crucial in the reaction, aso ther counter ions (PF 6 À ,T fO À , Cl À )r esulted in no stilbenef ormation.D uring catalysts creening, the [CpRu] + system was found to be less active than the [Cp*Ru] + fragment, which implies that arene exchange is ratedetermining, as am ore electron rich metal centre is expected to lead to weaker h 6 -arene coordination.

Reactionscatalytic in nickel
Beyondr eactions catalytic in Ru, several examples have been reported in which p-arene Ni intermediates are implicated. In a series of papers Hartwig reported the hydrogenation of aryl ethersw ith H 2 to yield aryl alcoholsa nd unsubstituted arenes ( Figure 8B), using catalytic Ni(COD) 2 anda nN-heterocyclic carbene ligand. [61,62] In the reaction, the aryl ether coordinates to aN i 0 centre via h 6 -coordinationt of orm intermediate 58 a.T he p-coordination activates the aryl ether towards an oxidative addition to the Ni centre( 58 b)( likely via an h 2 intermediate [63] ), before reaction with H 2 leads to release of the aryl alcohol and regeneration of an h 6 -coordinated unsubstituted arene (58 c). Finally,a rene exchange with the more electron rich aryl ether starting materialc ompletes the catalytic cycle. [62] Using very similar catalytic conditions, aryl fluorides were coupled with secondarya mines to give substituteda nilines ( Figure 8C). [64] While no direct evidencef or h 6 -coordination was provided, an oxidative addition pathway was proposed and based on Hartwig's subsequentwork, a p-arene intermediate preceding oxidative addition seemsh ighly likely.T he scope of this reactionw as extended to include primary amines in a study led by Iwai andS awamura. [65] Again, aN i 0 -based catalyst was employed, but bulky bis(phosphine) ligands were used in-stead of N-heterocyclicc arbenes,g iving selectivityf or formation of secondary over tertiary amines.

Reactionscatalytic in niobium
As ingle example hasb een presented in the literature in which Nb p-arene intermediates have been identified as key reaction intermediates. [66] Aryl fluorides undergo arene exchange with Nb III complex 60 a to give 60 b,w hich undergoes oxidative addition to form aryl-Nb V intermediate 60 c.T his species reductively eliminates in the presence of stoichiometric phenyl silane to give an overall catalytic hydrodefluorination (Figure 8D).

Perspectives
Whilst progress has been made over the past decade in developing catalysis via p-arene intermediates, limitations still remain,w ith most reactions suffering from low TONs andp oor scope of reactivity.T hese factors must be improved upon if these reactions are to competew ith catalytic transformations used in industrial processes. As previouslyd iscussed, factors that promote reactivity of ar ing typicallyi nhibiti ts ability to undergo arene exchange and mastering this fine balance is key to improving the TON of ac atalyst. Another factor complicating the arene exchange step is that often displacement of the product aromatic with the startingm aterial is disfavoured by their relative thermodynamic stabilities, particularly where electron rich nucleophilesa re involved. With both issues in mind,c areful consideration of substrates is necessary or methods to trigger arene exchange in stable complexes are required. The field of photocatalysis has grown rapidlyo ver recenty ears, due to advances in both theoretical understanding and practical instrumentation. It is well known that certain p-arenemetal complexes are susceptible to photoactivated destabilisation of the metal arene bond, therefore catalytic reactions in which light is used to trigger arene exchange should be entirely feasible. Despite this, there are almost no examples of this type of photocatalytic reactivity.As ingle reaction is known in which aR u-or Fe-catalysed cycloaromatisation of an enediynew ith g-terpinene as Hs ource is shown to proceed under irradiation (Figure 9). [67] The proposed catalytic mecha- nism ( Figure 9B)c onsistso facycloaromatisation to form an h 6 -coordinated arene complex, 61 b,t hen photolysis to give the free arene andt he complex [Cp*M(NCMe) 3 ] + (61 a), restarting the catalytic cycle. It is likely that the emergence of more photocatalytic protocols can pave the way towards solutions surrounding arene exchange, and developments here must be considered ah igh priority in the comingd ecade.

Conclusions and Outlook
This review was written with the objective of giving ac omprehensives ummary of recent advances in the reactivity of capping aromatics in p-arene metal complexes and transformations that are catalytic in metal. Despite the factt hat this field has been established since the 1950s, many significant developments have been made in the past 10-15years. Many new reactions that are stoichiometric in metal, both on the arene ring and its periphery have been reported, which highlight the significant change in reactivity of an arene upon coordination and the potential for stereochemical control. Furthermore, by combining the increased reactivity of h 6 -coordinated arenes with conditions that allow arene exchange, several efficient catalytic protocols have been developed.
Lookingf orwards, severalk ey milestones are still to be met in this field. Firstly,r eactions that are stoichiometric in metal would ideally be adapted such that the metal centre can either operate catalytically or allow for simple recovery of the activating metal.P hotolytic liberation of the capping arene and/or the use of heterogeneoussystems are the most promising methods to achieve recovery of the activating metal, but only Ru complexes currentlya llow for simple liberation of the coordinated arene via these methods. Whilst the development of catalytic reactions has been am ajor breakthrough in this field, more needs to be achieved to be competitive with industrial processes. In-depth mechanistic studies that help to identify active catalytic species and rate limiting reactions teps are crucial to realise this ambition. Focus on developing photocatalytic reactions also seems an important route forward. Particularly,a sa dvances are made in both theoretical and practical photochemistry,i ti sk ey for the field of p-arene metal complexes to take advantage of these developments. Overall, this field has ab right outlook and we look forward to the next decadeofd evelopments.