Carbon–carbon bond activation by Mg, Al, and Zn complexes

Examples of carbon–carbon bond activation reactions at Mg, Al, and Zn are described in this review. Several distinct mechanisms for C–C bond activation at these metals have been proposed, with the key C–C bond activation step occurring by (i) α-alkyl elimination, (ii) β-alkyl elimination, (iii) oxidative addition, or (iv) an electrocyclic reaction. Many of the known pathways involve an overall 2-electron redox process. Despite this, the direct oxidative addition of C–C bonds to these metals is relatively rare, instead most reactions occur through initial installation of the metal on a hydrocarbon scaffold (e.g. by a cycloaddition reaction or hydrometallation) followed by an α-alkyl or β-alkyl elimination step. Emerging applications of Mg, Al, and Zn complexes as catalysts for the functionalisation of C–C bonds are also discussed.


Introduction
Carbon-carbon (C-C) bonds are ubiquitous, making up the hydrocarbon skeleton of most organic molecules.Reactions that break strong C-C bonds are therefore of broad importance.For example, selective activation of C-C bonds affords a powerful method to alter the hydrocarbon scaffold of molecules. 1,2his opens the door for novel synthetic disconnections and routes to complex organic molecules of relevance to medicinal and materials chemistry.Reactions that break C-C bonds also underpin our global energy sector.Globally essential fuels (coal, crude oil, and biomass) are comprised of C-C bonds.Catalytic cracking of C-C bonds in hydrocarbon feedstocks, such as crude oil, converts high molecular weight alkanes to more valuable alkenes and medium-length hydrocarbons (e.g.][5] Reactions that break C-C bonds are challenging to achieve. 6C-C bonds are strong and non-polar.To give two examples: (i) ethane, the simplest linear alkane, has a homolytic bond dissociation energy 7 of 90.1 ± 0.1 kcal mol −1 , (ii) benzene has a calculated homolytic bond dissociation energy 8 of 147.0 kcalmol −1 .The increased thermodynamic stability of C-C bonds in aromatic rings is unsurprising given their p-character and electron delocalisation across the ring.C-C bonds are also sterically protected.They are oen buried within the molecular framework and the orbitals involved in bonding are kinetically inaccessible.As such chemoselectivity becomes a key issue, with surrounding C-H bonds oen the rst sites to react with reagents and catalysts that would otherwise be capable of breaking C-C bonds. 9re we dene C-C bond activation as a process in which the C-C bond of the s-framework breaks at a metal centre (M), creating at least one new M-C bond.While C-C bond functionalisation is dened as a process that breaks a C-C bond and transforms into two new C-X bonds (X = H, heteroatom).The activation of C-C bonds has been achieved on the surface of heterogeneous catalysts, 10 within the active sites of enzymes, 11,12 and under homogeneous conditions using metal complexes. 13,147][18] Oen model substrates that contain weakened C-C bonds and/or extensive ring strain are studied. 191][22] Reactivity tends to follow established mechanisms (Scheme 1).
(A) b-Alkyl elimination, wherein a metal bound alkyl ligand is fragmented into the corresponding metal alkyl and alkene units. 23,24B) Oxidative addition, wherein the C-C bond is cleaved by addition to a low oxidation state metal complex, increasing the metal oxidation state by two and creating two new M-C bonds. 17C) Cycloaddition between a hydrocarbon and metal reagent, creating a strained metallocycle which can then undergo C-C bond activation (e.g. through a-elimination or an electrocyclic reaction).25,26 Though important progress is being made toward transition metal mediated C-C bond activation, there is an increasing drive away from late transition metal-based systems.Late transition metals are commonly expensive and toxic, with further issues regarding the sustainability and ethics of the mining practices used to obtain the requisite minerals for Chemical Science REVIEW rening.27,28 Main-group metals (e.g.Mg, Al) along with the posttransition metal Zn are promising alternatives to their transition metal counterparts for applications in synthesis and catalysis.These elements are commonly earth-abundant, inexpensive, and more widely distributed in the Earth's crust compared to the late transition metals.29 They are non-toxic and accordingly safer to handle.For some (e.g.Al) there are even established networks and processes for recycling, auguring well for a future circular economy.
In this review, we summarise the current examples of C-C bond activation with Mg, Al, and Zn complexes.The scope of the review is limited to these emerging systems with a specic focus on mechanism and understanding.To the best of our knowledge there are no well-dened examples of C-C bond activation with heavier main group (Ca-Ba, Ga-Tl, Pb), or post-transition (Cd-Hg) metals.A limited number of examples of metal free C-C bond activation have been reported for systems using frustrated Lewis pairs, 30 boron-, 31,32 silicon-, [33][34][35] phosphorous, 36,37 and organic-compounds. 38These examples with nonmetals or semi-metals are not the focus of this review and are covered elsewhere. 39The discussion is split into three distinct approaches, namely b-alkyl migration, oxidative addition, and those initiated by cycloaddition reactions.Through discussion of mechanism, we aim to highlight the divergent chemistry shown by these complexes compared to their transition metal counterparts and touch on the potential implications in synthesis.

b-Alkyl elimination at Mg and Zn metal centres
One of the earliest reports of C-C s-bond activation by any metal appears to proceed through a b-alkyl migration mechanism at an aluminium centre.In 1960, Pfohl reported the thermolysis of tris(neo-pentyl)aluminium [Al{CH 2 C(Me) 3 } 3 ] 1 at high temperature (200 °C). 40The reversible stoichiometric formation of iso-butene gas and trimethylaluminium was observed via sp 3 C-C s-bond activation, presumed to occur through a b-methyl migration reaction (Scheme 2).The release of three equivalents of iso-butene gas provides an entropic driving force for the forward reaction.
In 1999, Dakternieks and co-workers reported a related reaction at a Sn complex, observed during fragmentation in a mass spectrometer. 41Application of a high cone voltage (>60 V) to a acetonitrile solution of the tris(neo-pentyl)stannyl cation [Sn{CH 2 C(Me) 3 } 3 ] + 2 showed formation of methyl tin cations and release of isobutene gas.Reaction of the deuterium labelled analog [Sn{CD 2 C(Me) 3 } 3 ] + showed the formation of isobutene gas with the alkene protons D-labelled, consistent with a b-alkyl elimination process.An alternate pathway involving homolysis of the Sn-C bond to form a neo-pentyl radical that fragments to iso-butene and a methyl radical that can recombine with Sn, was not ruled out and cannot be discounted under fragmentation conditions in the mass spectrometer.
In 2020, we reported C-C s-bond cleavage of strained alkylidene cyclopropanes using magnesium reagents. 42Reaction of the b-diketiminate stabilised magnesium(I) dimer [Mg{CH {C(CH 3 )NMes} 2 }] 2 (Mes = 2,4,6-trimethylphenyl) [43][44][45][46] 3 with alkylidene cyclopropanes 4a-b and subsequent addition of dimethylaminopyridine (DMAP) led to the corresponding ringopened products 5a-b$DMAP (Scheme 3).DMAP was used to trap and help crystallise the products and is not thought to participate in the mechanism of C-C s-bond activation.DFT calculations support a stepwise mechanism starting with 1,2addition of the Mg-Mg s-bond to the alkene. 47This step places one of the Mg sites in a suitable position to facilitate b-alkyl migration.b-Alkyl migration from the 1,2-dimagnesio-ethane intermediate is then a relatively facile process (DG ‡ 298 K = 12.7 kcal mol −1 ), yielding the observed products.
This work was extended to include reaction of the related magnesium(II) hydride complex 6 [Mg(m-H){CH{C(CH 3 ) NDipp} 2 }] 2 (Dipp = 2,6-diisopropylphenyl) with the same set of substrates (Scheme 3, bottom). 48,49Stoichiometric reaction of 6 with methylidene cyclopropane (7a) and methylidene cyclobutane (7b) yielded the ring-opened alkyl magnesium complexes 9a and 9b in good yields.Though no intermediates were observed spectroscopically, DFT calculations and related literature 23,50,51 supported a hydromagnesiated intermediate 8a-b as a prerequisite to b-alkyl elimination and thus C-C s-bond activation.Additional evidence for the hydromagnesiated intermediates was gathered through reaction of unstrained methylidene cyclopentane (7c) and methylidene cyclohexane (7d) with 6, which formed the hydromagnesiated products 8c-d in high yields. 52Calculated activation barriers for s-bond C-C bond cleavage for ve and six-membered rings were unfeasible under the reaction conditions (DG ‡ 298 K > 40 kcal mol −1 ), indicating that the release of ring strain in the three-and four-membered systems is an important driving force for the reaction.
The analogous zinc hydride complex [ZnH{CH{C(CH 3 ) NDipp} 2 }] 53 10 was shown to react with methylidene cyclopropane 7a in a similar fashion. 49The resulting zinc alkenyl complex 12 was isolated in high yield and characterised.In the case of zinc, the proposed hydrozincated intermediate Activation strain analysis 54,55 was used to explain the differences in reactivity between the analogous zinc and magnesium hydride complexes.Namely, that magnesium was observed to ring open cyclobutane rings, whereas zinc was not.The more electropositive metal (Mg) was shown to be better able to stabilize the hydrocarbon fragment at the C-C activation transition state, lowering the kinetic barrier relative to Zn. 49 6 and 10 have an identical ligand coordination, as such it can be concluded that chemoselectivity in these reactions can be controlled through choice of the metal.
Reaction of the magnesium alkenyl complex 9a with an excess of phenyl silane (PhSiH 3 ) led to formation of the linear and cyclic silane compounds 13-14 and reformation of magnesium hydride 6.A catalytic protocol for the hydrosilylation of strained s-C-C bonds was developed from these ndings. 42,49,56,57Reaction of 4ab and 7a-b with excess phenyl silane and 10 mol% of 6 showed high conversion to the respective cyclic silanes 14-15.In the case of 4b, catalytic hydrosilylation yields a mixture of E and Z stereoisomers of the products 16-17, with a ratio of E : Z of 1 : 1.1.Scheme 5 shows the proposed catalytic cycle, each step of which is supported by experimental and computational data.The stepwise process follows: (i) hydromagnesiation of the alkene through a 1,2-insertion reaction of the magnesium hydride to the alkene (ii) b-alkyl migration; (iii) s-bond metathesis to regenerate magnesium hydride catalyst 6 and the linear silane.The thermodynamic products 14-15 are likely formed from an intramolecular hydrosilylation also catalysed by the magnesium complex 6.The related zinc complex 10 was unable to catalyse the hydrosilylation of the s-C-C bond of 7a, again highlighting the divergent reactivity of main-group and post-transition metals in these systems. 49he most likely origin of these differences is the s-bond metathesis step of the proposed catalytic cycle which while operating with Mg, is likely too slow to facilitate turnover with Zn.

Oxidative addition at aluminium centres
Oxidative addition, and its microscopic reverse, reductive elimination, are some of the most fundamental  In 2020, Kinjo and co-workers reported an aluminyl anion stabilised by a cyclic (alkyl)(amino) ligand, prepared by potassium graphite reduction of the corresponding aluminium dimer in the presence of 12-crown-4. 66The resulting aluminyl anion 18 [Al{NAd(CH) 2 C(SiMe 3 ) 2 }][K(12-C-4) 2 ] was shown to react with biphenylene at room temperature over the course of four hours (Ad = 1-adamantyl, 12-C-4 = 12-crown-4).Oxidative addition of the weakest C-C s-bond in biphenylene (in the strained four membered ring) was observed (Scheme 6).The metallocyclic anionic complex 19 was isolated in moderate yield (33%) and crystallographically characterised.The overall reaction can be categorised as a two-electron oxidative addition reaction at Al, from Al(I) to Al(III).Oxidative addition of the central four membered ring of biphenylene is well known for most transition metals, with this work extending the concept to main-group metal complexes for the rst time.DFT calculations, performed by Zhu and co-workers, suggest C-C s-bond activation of benzene by 18 could become both kinetically and thermodynamically favourable through addition of electron withdrawing groups onto benzene. 67In practice though, inclusion of additional functionality raises the issue of chemoselectivity; most of these functional groups would contain C-X (X = heteroatom) bonds that are likely to react in preference to the C-C bond.

C-C bond activation initiated by cycloadditions
In 2020, we reported the reaction of a b-diketiminate stabilised aluminium(I) nucleophile 71  ).The data suggests the key factor for C-C s-bond scission is not dependent on a redox reaction at the aluminium centre, rather on the installation of the electropositive Al atom in the correct position on the hydrocarbon scaffold to facilitate the a-alkyl migration rearrangement.
In 2021, our group reported the reaction of 20 with biphenylene. 75This was the rst report of chemoselective C-C bond activation of biphenylene, and a rare example where the substrate bias is overcome by reagent control.Reaction of two equivalents of 20 with biphenylene and heating to 100 °C yielded a mixture of metallocyclic complexes 25 and 26 in which aluminium(III) centres are incorporated in ve-membered rings (Scheme 8). 25 and 26 are derived from the cleavage of the C 2 -C 3 and C 4 -C 5 bonds in the C 6 ring of biphenylene, respectively.These complexes can be separated.Heating puried samples of either product showed that they did not interconvert under the reaction conditions.
DFT calculations suggest an initial (4 + 1) cycloaddition reaction between 20 with biphenylene, 76 specically a [ p 4 s + n 2 s ] cycloaddition, yielding a highly strained and dearomatised hydrocarbon scaffold.The intermediate 23 can be isolated from the stoichiometric reaction of 20 with biphenylene at 25 °C for seven days.From 23, DFT calculations suggest a pathway for addition of a second equivalent of 20 to the C 2 -C 3 position and a subsequent concerted rearrangement to the more thermodynamically favourable isomer 24.The isomerisation is likely driven by the interchange of the three-and ve-membered rings within the rst intermediate to two four-membered rings in the second intermediate, relieving ring strain in the system.From 24, two similar energy pathways to products 25 and 26 are proposed, via either C-C bond cleavage and subsequent 1,3sigmatropic shi, or a 1,3-sigmatropic shi followed by C-C bond cleavage.Both pathways are highly exergonic, consistent with the nonreversible formation of the products observed experimentally.A direct oxidative addition of the central C 1 -C 7 s-bond of biphenylene to 20 was calculated to occur by a high activation barrier (DG ‡ 298 K = 42.0 kcal mol −1 ), likely to be inaccessible under the reaction conditions.Further calculations using activation strain analysis suggest that the inaccessible energy barriers for oxidative addition are likely a result of the strain required to achieve orbital overlap between the aluminium complex's lone pair and C 1 -C 7 s*-orbital in biphenylene.
3][74]   In 2019, Aldridge, Goicoechea, and co-workers reported the reversible room temperature C-C bond activation of benzene using a nucleophilic aluminium complex (Scheme 10). 68Reaction of [K(2.2.2-crypt)][(NON)Al] (31, where NON = 4,5-bis(2,6-diisopropyl-anilido)-2,7-di-tert-butyl-9,9-dimethylxanthene) with benzene at room temperature gave near quantitative formation of the corresponding aluminium(III) cycloheptatriene 33.A cross-over experiment in which deuterium labelling C 6 D 6 was added to 31 showed that the reaction is reversible, as evidenced by formation d 6 -33 and C 6 H 6 ðDG ð298 KÞ ¼ À4:0 kcal mol À1 Þ: Addition of Me 2 -SnCl 2 to 33 generated the Z,Z,Z-isomer of the dimetallated heptatriene, Me 2 ClSnCH]CH-CH]CH-CH]CHSnClMe 2 (34), derived from benzene.The aluminocycle 33 formed by C-C bond activation was shown to be a kinetic product that formed reversibly.When samples were heated to 80 °C non-reversible C-H activation of the benzene ring was observed.A subsequent computational investigation by Fernández and co-workers explored the competing C-C and C-H bond activation of benzene by 31 using a combination of activation strain and energy decomposition analyses. 69Calculations support C-C bond activation as a kinetic pathway, as observed experimentally.The overall oxidative addition occurs through a stepwise mechanism, initiated by a (2 + 1) 70

Chemical Science Review
an increase in the HOMO energy the major contribution to the change.
Further calculations were performed to investigate a likely reaction mechanism to form pentalene complex 41a; for computational cost, a truncated analog of 40 was used [Al(NHC ′ )Ar ′ ] (NHC ′ = 1,5-dimethylimidazol-2-ylidene; Ar ′ = 2,6-C 6 H 3 Xyl 2 , Xyl = 2,6-dimethylphenyl).Two potential mechanisms were investigated computationally.The authors comment that both pathways are feasible with low and reversible energy barriers for C-C bond activation and are likely competing.The rst pathway, analogous to the reaction of 20 with biphenylene, 75 proceeds via a (4 + 1) cycloaddition by the aluminylene with benzene, followed by a ( 2

Conclusions and perspective
Carbon-carbon bond activation facilitated by main-group and post-transition metal complexes is gathering increasing attention.In this regard, it is notable that many of the emerging applications of low-valent aluminium in C-C bond activation rely on low-oxidation state complexes with coordinated ligands (e.g.NHCs).The coordination event not only lowers the HOMO-LUMO gap it also changes the geometry at the metal centre.Both may be important in reaching accessible transition states for C-C bond activation that might not otherwise be possible with the ligand-free counterparts.Similarly, cooperative effects between two or more metals offer alternative pathways to break C-C bonds with reagents that are constrained to a certain set of orbital interactions.Bimetallic pathways have been invoked in several of the systems known to date, with two metals acting in concert; binding, distorting, and destabilising hydrocarbon frameworks to achieve C-C bond activation.
In the immediate future, it is likely that new and interesting examples of C-C bond activation with main group and posttransition metals will be discovered.Investigation of lowvalent aluminium reagents appears to be a particularly fertile area.Systematic studies that aim to generate an understanding of why examples of C-C bond activation with certain metals are so prevalent, and what factors inuence reactivity (e.g.coordination geometry, orbital energies, orbital symmetry, electronegativity of M, M-C bond dissociation energies) will help the eld develop.Only a small number of main group and posttransition metal elements have been reported to facilitate C-C bond activation.Investigation of complexes of electrophilic main group metals such as those of Ca, Sr, Ba, Ga, In, Sn, and Pb is warranted and may bring with it new mechanistic insight and/or opportunities to control selectivity by tuning the metal site.The scope of reactivity described so far spans some of the most activated strained cycloalkanes and least reactive aromatic carbon rings.There is enormous opportunity in the middle ground.Expansion of examples of C-C bond activation to medium and large cycloalkane rings along with fragmentation of branched and linear alkane chains are obvious targets for the eld.
Catalytic protocols for C-C bond functionalisation e.g. through hydrosilylation are beginning to emerge.There is a clear need for development of new catalysts for C-C bond functionalisation.The ability to alter hydrocarbon scaffolds of complex organic molecules and to valourise simple hydrocarbons or aromatics through catalysis are particularly attractive approaches that have long been associated with late transition metals.In the longer term, such catalytic transformations could underpin sustainable chemical manufacturing practices including the valourisation of molecules from biomass or the recycling of hydrocarbon-based polymers.The efforts described above suggest that main group systems have the potential to make important contributions in these areas that complement transition metal systems while also addressing key aspects of element scarcity, supply chain risk, and sustainability.
11 was observed spectroscopically (Scheme 4).Diagnostic resonances in the 1 H NMR spectra at d = −0.39 to −0.36 and d = 0.15 to 0.20 ppm were assigned to 11 through application of HSQC and TOCSY NMR methods.DFT calculations support a stepwise hydrometallation and subsequent b-alkyl elimination pathway.The activation barrier for C-C cleavage was calculated as DG ‡ 298 K = 35.2kcal mol −1 , in line with the high temperature conditions required for the reaction.

Scheme 8
Scheme 8 Reaction of aluminum(I) nucleophile 20 with biphenylene, giving a mixture of products formed via C-C s-bond cleavage.Ar = 2,6-diisopropylphenyl; NMR yield shown for product mixture.
Scheme 10 Reversible insertion of aluminium(I) complex 31 into the C-C bond of benzene.
+ 1) cycloaddition from another equivalent of 40 on the opposite face of the benzene molecule to create a bimetallic complex 43.Rearrangement and concomitant C-C bond activation of the benzene unit yields 41a in an overall exergonic process ðDG ‡ 298 K ¼ 25:8 kcal mol À1 ; DG 298 K ¼ À38:1 kcal mol À1 Þ: The second pathway involves an initial formal insertion of aluminylene 40 into the C-C bond of benzene via an initial (2 + 1) cycloaddition forming an aluminocyclopropane intermediate 44.Reaction of a second equivalent of 40 with this intermediate again facilitates C-C bond cleavage, yielding the observed product 41a (DG ‡ 298 K = 17.4 kcal mol −1 ).