Computational mechanistic elucidation of the intramolecular aminoalkene hydroamination catalysed by iminoanilide alkaline-earth compounds.

DOI: 10.1002/chem.201500233

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Computational Mechanistic Elucidation of the Intramolecular Aminoalkene Hydroamination Catalysed by Iminoanilide AlkalineEarth Compounds Sven Tobisch*[a] Abstract: A comprehensive computational exploration of plausible alternative mechanistic pathways for the intramolecular hydroamination (HA) of aminoalkenes by a recently reported class of kinetically stabilised iminoanilide alkalineearth silylamido compounds [{N^N}Ae{N(SiMe3)2}·(thf)n] ({N^N} = iminoanilide; Ae = Ca, Sr, Ba) is presented. On the one hand, a proton-assisted concerted N¢C/C¢H bond-forming pathway to afford the cycloamine in a single step can be invoked and on the other hand, a stepwise s-insertive pathway that involves a fast, reversible migratory olefin 1,2-insertion step linked to a less rapid, irreversible metal¢C azacycle tether s-bond aminolysis. Notably, these alternative mechanistic avenues are equally consistent with reported key experimental features. The present study, which employs a thoroughly benchmarked and reliable DFT methodology, supports the prevailing mechanism to be a stepwise s-insertive pathway that sees an initial conversion of the {N^N}Ae silylamido into the catalytically competent {N^N}Ae amidoalkene compound and involves thereafter facile and reversible

Introduction Catalytic hydroamination (HA), the direct addition of an N¢H bond across an unsaturated carbon–carbon linkage, offers facile access to industrially relevant organonitrogen commodity and fine chemicals in a waste-free, highly atom-efficient and green manner and thus is a topic of considerable interest in both academia and industry.[1] Intramolecular HA constitutes a particularly powerful and concise route to functionalised nitrogen heterocycles. Initially dominated by the discovery of organolanthanide catalysts,[1k, 2] present-day intramolecular HA research activities are wide ranging, covering the entire periodic table, from early d-block metals,[3–5] 4f[2] and 5f elements,[6] to late d-block[7, 8] and coinage metals.[7b, n, 9]

[a] Dr. S. Tobisch University of St Andrews, School of Chemistry Purdie Building, North Haugh, St Andrews Fife KY16 9ST (United Kingdom) Fax:(+ 44) 1797-383-652) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500233. Chem. Eur. J. 2015, 21, 6765 – 6779

insertive N¢C bond-forming ring closure, linked to irreversible intramolecular Ae¢C tether s-bond aminolysis at the transient {N^N}Ae alkyl intermediate. Turnover-limiting protonolysis accounts for the substantial primary kinetic isotope effect observed; its DFT-derived barrier satisfactorily matches the empirically determined Eyring parameter and predicts the decrease in rate observed across the series Ca > Sr > Ba correctly. Non-competitive kinetic demands militate against the operation of the concerted proton-assisted pathway, which describes N¢C bond-forming ring closure triggered by concomitant amino proton delivery at the C=C linkage evolving through a multi-centre TS structure. Valuable insights into the catalytic structure–activity relationships are unveiled by a detailed comparison of [{N^N}Ae(NHR)] catalysts. Moreover, the intriguingly opposite trends in reactivity observed in intramolecular (Ca > Sr > Ba) and intermolecular (Ca < Sr < Ba) HA catalysis for the studied family of iminoanilide alkaline-earth amido catalysts are rationalised.

Research efforts aimed at the development of main group metal-based catalyst systems have intensified rather recently.[10–12] The broad similarity between divalent s-block elements and d0 tripositive lanthanides (Ln) in supporting highly ionic and non-directional bonding to an effectively redox-inactive metal centre[13] has provoked particular interest in alkalineearth (Ae) metal complexes as potential HA catalysts in recent years.[11] Kinetically stabilised iminoanilide alkaline-earth metal compounds [{N^N}Ae{N(SiMe3)2}·(thf)n] (Ae = Ca, Sr, Ba) have been recently reported by Sarazin and co-workers to competently mediate the cyclisation of aminoalkenes with reaction rates decreasing across the series Ca > Sr > Ba.[14] It is worth mentioning that the identical family of precatalysts has moreover been demonstrated to catalyse the HA of styrene with exceptionally high activities, but displays the reverse trend in activity (Ca < Sr < Ba).[15a] Scheme 1 displays the principal features of the most plausible of the several mechanistic proposals for intramolecular HA of various substrate classes promoted by compounds containing s-block, early d-block and lanthanide elements that have emerged over the years. The starting material needs to undergo an initial transformation into the catalytically competent metal amido compound, which could well favour the former

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Full Paper was thus suggested for aminoalkene cyclohydroamination by a variety of catalyst systems; among them tris(oxazolinyl)borate {ToM}MgII alkyl,[11f] diketiminate[11h] and iminoanilide[14] alkaline-earth catalysts, but also cyclopentadienyl–bis(oxazolinyl)borate {CpoM}YIII alkyl[3p] compounds. Recent computational studies described the concerted mechanism as a viable but energetically noncompetitive alternative in the presence of an operative s-insertive mechanism for {ToM}MgII alkyl[17a] and {CpoM}YIII alkyl[17b] compounds. A similar concerted proton-assisted pathway for HA of styrene with pyrrolidine by iminoanilide alkaline-earth compounds was also found computationally to be energetically more demanding than a stepwise s-insertive pathway. However, further complementary experimental[18a] and computational[18b] mechanistic studies have provided compelling evidence for the operation of a protonScheme 1. Plausible mechanistic pathways for iminoanilide alkaline-earth-catalysed intramolecular aminoalkene assisted concerted mechanism hydroamination, exemplified for [{N^N}Ae(NHR)·(NH2R)2] alkaline-earth amido 3’·(S)2 as the catalytically competent compound and prototype 2,2’-dimethylpent-4-en-1-amine substrate (S 1) ({N^N}¢ = [ArN(o-C6H4)C(H)=NAr]¢ with for aminoalkene HA by Ar = 2,6-iPr2C6H3). a [ZrIV(NHR)2] catalyst with a sterically encumbering tethered bis(ureate) ligand. Precise knowledge of both the operative mechanism and the catalytic structure–activity thermodynamically, after which the process is traditionally relationships are required for the rational design of improved thought to proceed in a stepwise manner involving first the inHA catalysts. In light of the residual uncertainty as to which of sertion of an unsaturated C¢C linkage into the metal¢Namido sbond (3·(S)2 !4·(S)2 ; S = substrate) and subsequent metal¢C sthe competing pathways in Scheme 1 prevails and also in the bond aminolysis at the metal alkyl intermediate (4·(S)2 !5·S). It absence of a precise delineation of structure–activity relationis commonly believed for this s-insertive mechanism ships, we have employed density functional theory (DFT) calcu(Scheme 1, cycle A) that insertive cyclisation is turnover limitlations as an established and predictive means to study reacing, with M¢C s-bond aminolysis assumed to be significantly tion mechanisms and to guide rational catalyst design. The faster.[1k, 2b] However, the large kinetic isotope effects (KIEs) for present study scrutinises rival mechanistic pathways for intraHA of aminoalkenes, for instance by organolanthanide catamolecular hydroamination of the prototype 2,2’-dimethylpentlysts,[2b] clearly militates against the traditional view of the s-in4-en-1-amine substrate (S 1) by competent iminoanilide [{N^N}Ae{N(SiMe3)2}·(thf)n] alkaline-earth silylamido precatalysts sertive mechanism and suggests an alternative proton-assisted pathway that evolves through a multicentre transition state 2 (Ae = Ca, Sr, Ba; {N^N}¢ = [ArN(o-C6H4)C(H)=NAr]¢ with Ar = (TS) structure describing concerted N¢C/C¢H bond formation 2,6-iPr2C6H3), which were recently reported (Scheme 2).[14] No [2b, 6c, 16] proceeding outside of the metal’s immediate vicinity. structural simplifications of any kind have been imposed for any of the key species involved. This process proceeds with Commencing from the {N^N}Ae amido substrate adduct a substantial primary KIE with the calcium compound display(3·(S)2), the cycloamine is delivered in a single step via the ing the highest activity and reaction rates decreasing across proton-assisted pathway (Scheme 1, cycle B), thus contrasting the series Ca > Sr > Ba, in contrast with the opposite trend in the s-insertive pathway. reactivity (Ca < Sr < Ba) observed for HA of styrene with pyrroliThe proton-triggered concerted N¢C/C¢H bond-forming dine by the same family of precatalysts.[15] Kinetic studies unmechanism received particular recognition in recent years and Chem. Eur. J. 2015, 21, 6765 – 6779

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Full Paper {N^N}Ca(NHR)-mediated HA of aminoalkene S Catalyst initiation Scheme 2. Intramolecular HA of a primary 2,2’-disubstituded aminoalkene by iminoanilide [{N^N}Ae{N(SiMe3)2}·(thf)n] alkaline-earth silylamido compound 2. (Ae = Ca (n = 1), Sr (n = 2), Ba (n = 2); {N^N}¢ = [ArN(o-C6H4)C(H)= NAr]¢ with Ar = 2,6-iPr2C6H3).

dertaken at the [{N^N}Ba{N(SiMe3)2}·(thf)2] precatalyst determined a moderate turnover-limiting barrier of 23.7(2.1) kcal mol¢1 (DG at 298 K) for cyclohydroamination of substrate S.[14] The DFT methodology employed (dispersion-corrected B97D3 in conjunction with basis sets of triple-z quality and a sound treatment of bulk solvent effects) simulated authentic reaction conditions adequately and mechanistic analysis is based on Gibbs free-energy profiles. Furthermore, the validity of the computational protocol employed for reliably mapping the energy landscape of alkaline-earth-mediated HA has been substantiated before[15b] and this has allowed mechanistic conclusions with substantial predictive value to be drawn. The comprehensive mechanistic examination provided herein supports the prevailing mechanism to be a stepwise sinsertive pathway that sees an initial conversion of the {N^N}Ae silylamido starting material into the catalytically competent {N^N}Ae amidoalkene compound and entails thereafter facile and reversible insertive N¢C bond-forming ring closure, linked to irreversible intramolecular Ae¢C tether s-bond aminolysis at the transient {N^N}Ae alkyl intermediate. Turnoverlimiting protonolysis is consistent with the substantial primary KIE observed; its DFT-derived barrier satisfactorily matches the empirically determined Eyring parameter and predicts the decrease in rate observed across the series Ca > Sr > Ba correctly. On the other hand, an energetically more demanding kinetic profile militates against the operation of a concerted protonassisted pathway for aminoalkene cyclisation for the family of iminoanilide alkaline-earth amido catalysts in hand.

Results and Discussion The present study is divided into several parts. The first part entails a thorough scrutiny of all the relevant elementary steps of alternative mechanistic pathways in Scheme 1 for the bestperforming calcium precatalyst, with special attention devoted to assessing the affinity for substrate association for each individual species. The key features of the Ca¢Namido stepwise sbond insertive and concerted proton-assisted pathways of Scheme 1 are analysed and the two mechanistic alternatives are compared and contrasted. The effect of the alkaline-earth metal (Ae = Sr, Ba) on the energetics of relevant elementary steps is scrutinised thereafter. Finally the insights into structure–activity relationships gained herein are compared with the finding of a previous study[15b] on intermolecular HA by the same family of precatalysts. Chem. Eur. J. 2015, 21, 6765 – 6779

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Effective HA entails the initial transformation of the THF-coordinated iminoanilide calcium starting material [{N^N}Ca{N(SiMe3)2}·(thf)] (2) into the catalytically competent calcium amido compound [{N^N}Ca(NHR)]. The ability of 2 to effect protonolytic Ca¢Namido s-bond cleavage, although it is unlikely to be turnover limiting, will determine the amount of catalytically competent calcium amido species available for catalytic turnover, and hence profoundly influence the performance in HA catalysis. The THF-coordinated calcium silylamide 2·T, featuring a single THF molecule, is found energetically favourable relative to a bis-THF adduct 2·(T)2 (Figure 1), in agreement with ex-

Figure 1. Amine association at the iminoanilide calcium silylamido starting material 2.[19, 20a]

periment. It provides, moreover, some confidence in the predictive abilities of the employed computational protocol (see the Computational Methodology section). Aminoalkene S binds more strongly at the calcium centre in 2 than THF, whereas the silylamine HN(SiMe3)2 (ASi) binds considerably more weakly (Figure 1). It is worth mentioning that {N^N}Ca silylamido is capable of accommodating two molecules of either primary or secondary amine, with 2·(S)2 and 2·S·ASi found to be thermodynamically preferred to its mono-amine analogues, although association of a third amine molecule is found to not be achievable. The DFT-derived order of stability of donor molecule adducts (Figure 1) is corroborated further by the X-ray structural characterisation of [{BDI}Ca{N(SiMe3)2}·(thf)] and [{BDI}Ca{N(SiMe3)2}·(S)2] featuring a b-diketiminate calcium ligation.[11j] After the initial facile and downhill displacement of THF by S, the Ca¢Namido s-bond aminolysis commencing from substrate adducts 2·(S)n (n = 1, 2) evolves through a metathesistype TS that decays thereafter into substrate-free and substrate-coordinated forms of the calcium amido catalyst complex through facile liberation of silylamine. Figure 2 reveals that 2·T + SQ3’ (+ THF + HN(SiMe3)2) and 2·T + 2SQ3’·S (+ THF + HN(SiMe3)2) pathways with one or two substrate molecules involved appear equally viable. However, the participation of a spectator substrate molecule via 2·T + 2SQ3’·S (+ THF + HN(SiMe3)2) stabilises all the involved species (but to dif-

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Figure 2. Ca¢Namido s-bond aminolysis at 2 by substrate (S 1).[19, 20a]

ferent extents) and thus favours this pathway relative to 2·T + SQ3’ (+ THF + HN(SiMe3)2) on both thermodynamic and kinetic grounds. It has an affordable barrier of 14.0 kcal mol¢1 (relative to 2·(S)2 as the prevalent encounter species) and excess substrate further stabilises the {N^N}Ca amidoalkene compound through formation of a bis-amine adduct 3·(S)2. Given its relatively modest kinetic demands, catalyst initiation through protonolytic Ca¢Namido s-bond cleavage proceeding via the dominant 2·T + 2SQ3’·S (+ THF + HN(SiMe3)2) pathway followed by rapid association of another substrate molecule to generate the thermodynamically prevalent 3·(S)2 form of the catalytically competent {N^N}Ca amidoalkene compound is a kinetically mobile equilibrium, which, however, lies on the left. Alkaline-earth amido compounds are known to form dimeric species, but calcium amido species 3’ or 3’·S exhibit no pronounced propensity towards dimer formation. As shown in Figure 2, dimer 3ad is more favourable than its substrate adduct 3ad·S for a compact calcium centre, but both are found to be at higher free energy relative to the prevalent {N^N}Ca amido species 3·(S)2. The predicted gap of 4.9 kcal mol¢1 between 2·(S)2 and 3·(S)2, in favour of the former, indicates that the ineffectual protonolytic expulsion of the silylamido ligand in 2 due to unfavourable thermodynamics limits the population of the {N^N}Ca amido compound available to catalyst turnover. The [{N^N}Ca(NHR)] compound Amine substrate (S), silylamine (ASi) or cycloamine product (P), together with THF molecules, compete for association at calcium in the catalytically competent amidoalkene compound. The association can be envisaged to occur in various ways to give rise to a multitude of adduct species, all of which are expected to participate in rapid association/dissociation equiliChem. Eur. J. 2015, 21, 6765 – 6779

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bria.[19] Figure 3 collates the relative stabilities of various located species with one or two coordinated amine or THF molecules.[19c] A moderately sterically encumbering {N^N}Ca ligation renders donor molecule association at calcium affordable energetically and favours species with two coordinated donor molecules, like 3·(S)2, 3·S·P or 3·(T)2, over analogues with a single coordinated molecule. Of the various donor molecules, primary (S) and secondary (P) amines display a comparable propensity for binding at calcium (cf. 3·(S)2 and 3·S·P), whereas THF (T) is found to be less strongly bound. In contrast, the more bulky and somewhat less strongly donating silylamine (ASi), which is generated during catalyst initiation, forms only weakly stabilised adducts, and is thus unable to compete for association at the {N^N}Ca amido in the presence of amines S or P and THF. Further analysis of catalytically competent [{N^N}Ca(NHR)·(S)n] species reveals that the amidoalkene association pattern for substrate-free and substrate-coordinated species largely reflects the varying spatial demands around calcium. For substrate-free forms, species 3’ featuring an amidoalkene unit, which forms a weak chelate by orienting its double bond proximal to calcium, is thermodynamically preferred over 3 with a monohapto N-ligated amidoalkene unit. The gap becomes marginally smaller for mono-amine-coordinated species, again in favour of 3’·S over 3·S, but the order of relative stability becomes inverted for bis-amine adducts. With a further saturation of the coordination sphere around calcium by a second associated amine molecule, the tendency to form 3’·(S)2 decreases, such that 3·(S)2 prevails energetically. Overall DFT reveals that the strength of donor molecule association follows the order S P > T > ASi. The catalytically competent {N^N}Ca amidoalkene compound is predominantly present as bis-substrate adducts (3·(S)2 but also 3’·(S)2), together with less populated mono-substrate adducts (3’·S, 3·S) and substrate-free species (3’, 3). Forthcoming sections will scruti-

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Figure 3. Amine association at the catalytically relevant [{N^N}Ca(NHR)] compound.[19, 20b]

nise the propensity of the various 3’·(S)n, 3·(S)n species to participate in accessible pathways for catalytic turnover. The s-insertive mechanism The analysis of proposed alternative mechanistic scenarios starts with a thorough examination of the s-insertive mechanism (Scheme 1, cycle A) that involves migratory olefin 1,2-insertion into the Ca¢Namido s-bond proceeding at 3’·(S)n (n = 0– 2) and subsequent intramolecular protonolytic cleavage of the Ca¢C azacycle tether s-bond at the calcium alkyl intermediate by an metal bound amine molecule. In light of the pronounced aptitude of the {N^N}Ca amido to favourably bind additional amine molecules, it can reasonably be anticipated that viable pathways for insertive cyclisation see the participation of bound amine serving as a spectator, but effects intramolecular Ca¢C s-bond aminolysis thereafter.

(Scheme 3). A further trajectory describing a frontal olefin approach with two amine molecules residing in axial positions has been considered for 3’·(S)2 !4·(S)2 cyclisation. Common to all trajectories investigated is that N¢C bondforming ring closure evolves through a four-centre TS structure describing a metal-mediated olefin 1,2-insertion into the Ca¢ Namido s-bond that occurs at distances of approximately 2.0 æ for the emerging N¢C bond. Following the reaction path further, TS structures decay into the {N^N}Ca alkyl intermediate 4·(S)n, which has the azacycle bound to the alkaline earth through its methylene tether and the nitrogen donor centre. Figure 4 collates the condensed energy profiles for 3’·(S)n ! 4·(S)n insertive cyclisation proceeding via the most accessible pathways; the full account of all the studied pathways can be

Migratory olefin 1,2-insertion into the Ca¢Namido s-bond Several imaginable trajectories for insertive cyclisation featuring an axial or equatorial approach of the olefin unit that starts from 3’ or its mono- (3’·S) or bis-substrate (3’·(S)2) adducts have been examined Chem. Eur. J. 2015, 21, 6765 – 6779

Scheme 3. Alternative trajectories for migratory olefin 1,2-insertion into the Ae¢Namido s-bond at substrate adducts 3’·S (top) and 3’·(S)2 (bottom) of the catalytically competent {N^N}Ae amido compound.

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Full Paper ed spectator substrate molecules. Irrespective of comparable innate abilities to facilitate the process, N¢C ring closure at mono-substrate adducts or substrate-free species is distinctly less probable or completely prohibited, due to the unfavourable thermodynamic gap between 3’·(S)n species. The most accessible 33’·(S)2Q43·(S)2 pathway has a remarkably modest barrier of 11.9 kcal mol¢1 (relative to 3·(S)2) to overcome and is somewhat endergonic. It characterises insertive ring closure for a sterically moderately encumbered {N^N}Ca amidoalkene catalyst complex as a kinetically facile, reversible transformation that favours the reactant. Ca¢C azacycle tether s-bond aminolysis

Figure 4. Most accessible pathways for migratory olefin 1,2-insertion into the Ca¢Namido s-bond at 3’ and its substrate adducts 3’·S and 3’·(S)2.[19, 20b]

The {N^N}Ca alkyl intermediate that is generated via the most accessible 33’·(S)2Q43·(S)2 pathway for N¢C bond formation already has two substrate molecules bound at calcium, which are, moreover, favourably placed cis to the equatorial Ca¢C tether linkage. Notwithstanding this fortunate arrangement, several conceivable trajectories for intramolecular H transfer have been probed (Scheme 4) for {N^N}Ca alkyl species that are generated via 3’·SQ4·S and 3’·(S)2Q4·(S)2 pathways for insertive cyclisation. Aminolysis evolves through a metathesis-type TS structure that describes the cleavage of an already suitably polarised N¢ H bond and concurrent C¢H bond formation. The process to commence at 4·S and 4·(S)2 preferably proceeds through a trajectory that constitutes the cleavage of an equatorial calcium– alkyl s-bond by a proton released from an axially metal bound, hence N¢H activated, substrate molecule (Figure 5). All the other trajectories of Scheme 4 (the full account of which can be found in the Supporting Information, Figures S5–S7) are found to also be energetically viable, but are somewhat less likely to be traversed. Interestingly, 41·S and 43·(S)2 generated via preferably traversed pathways for insertive cyclisation with one or two spectator substrate molecules involved are precursor species for the most accessible 41·S!5 and 43·(S)2 !53·S aminolysis pathways. Hence, neither association of another substrate molecule or major structural reorganisation is required for protonolytic Ca¢C s-bond cleavage to occur at the

found in the Supporting Information (Figures S1–S4). The visual inspection of key species participating along these pathways provides no indication that a substantial structural reorganisation is required for the process to evolve from the directly associated precursor species 3x’·(S)n via TS structures [3x’·(S)n–4x·(S)n] to afford the respective {N^N}Ca alkyl species 4x·(S)n. Moreover, additional coordinated amine spectator molecules are unlikely to limit the accessibility of calcium by the double bond for a moderately spatially encumbering {N^N}Ca catalyst backbone. Hence, a sufficiently effective activation of the olefin unit towards a nucleophilic amido approach by its close interaction with the electropositive alkaline earth is maintained for pathways with one or two spectator substrate molecules participating. Indeed, pathways without (3’Q4, DG/ DG = 9.9/5.8 kcal mol¢1, relative to 3’), with one (31’·SQ41·S, DG/DG = 9.8/5.2 kcal mol¢1, relative to 31’·S) or two coordinated substrate molecules (33’·(S)2Q43·(S)2, DG/DG = 9.3/4.6 kcal mol¢1, relative to 33’·(S)2) exhibit intrinsic energy profiles of comparable magnitude. Hence, it is not the innate ability of 3’·(S)n species facilitating N¢C bond formation, but the thermodynamic penalty imposed on 3’ and 3’·S relative to 3’·(S)2 (Figure 3) that renders insertive cyclisation at 3’ or 3’·S less probable. Migratory olefin 1,2-insertion into the highly polar Ca¢Namido s-bond preferably proceeds through a trajectory featuring a frontal olefin approach via a planar four-centre TS structure, which benefits from the Scheme 4. Alternative trajectories for Ae¢C azacycle tether s-bond aminolysis at the alkaline-earth alkyl intermediparticipation of two coordinatate through pathways with one (top) or two (bottom) coordinated substrate molecules involved. Chem. Eur. J. 2015, 21, 6765 – 6779

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Full Paper benefit from the participation of excess amine through a relaytype mechanism. Similar to previous findings for a related tris(oxazolinyl)borate catalyst [{ToM}Mg(NHR)],[17a] route A proves to be distinctly more accessible than route B and is likely the dominant pathway for generation of 6·(S)n. Figure 6 collates the energy profiles for the most accessible pathways to commence from 5 and its mono-substrate adduct 5·S. It reveals that pyrrolidine a-proton abstraction preferably

Figure 5. Most accessible pathways for Ca¢C s-bond aminolysis at amine adducts 4·S and 4·(S)2 of the {N^N}Ca alkyl intermediate.[19, 20b]

{N^N}Ca alkyl intermediate. Similar to what is found for the insertive cyclisation step, the two 41·S!5 and 43·(S)2 !53·S pathways have an almost identical intrinsic barrier (relative to its direct precursor species) of 7.4 and 7.3 kcal mol¢1, respectively, and are driven by a thermodynamic force of comparable magnitude. However, the distinct stability gap between 41 and 43·S, in favour of the latter, renders 43·(S)2 !53·S the most accessible pathway for Ca¢Calkyl s-bond aminolysis (Figure 5). It features a modest barrier of 7.3 kcal mol¢1 (relative to 43·(S)2) and affords [{N^N}Ca(NHR)·(NHRR)] compound 5 in a process that is downhill by 15.1 kcal mol¢1 (relative to 43·(S)2). Incoming substrate S readily displaces the pyrrolidine at 53·S in an almost thermoneutral transformation (DG = ¢0.3 kcal mol¢1 for 53·S + SQ3·(S)2 + P), thereby completing cycle A in Scheme 1 with the regeneration of the catalytically competent {N^N}Ca amidoalkene compound for another catalyst turnover. Overall, the DFT-derived smooth energy profile shown in Figure 5 is indicative of a kinetically viable and exergonic, hence irreversible, intramolecular Ca¢Calkyl s-bond protonolysis step via the most accessible 43·(S)2 !53·S pathway. It is worth noting that the participation of a metal-bound spectator amine molecule is vital for aminolysis to be effective for the iminoanilide alkaline earth family of catalysts. The inaccessibility of the rival 41·S!5 pathway, despite its comparable innate abilities facilitating the step, has its origin solely in the thermodynamic gap between 41·S and 43·(S)2.

Figure 6. Most accessible pathways for conversion of {N^N}Ca amido cycloamine compound 5 into {N^N}Ca pyrrolide intermediate 6.[19. 20b]

takes place at 53·S, which is formed via the dominant 43·(S)2 ! 53·S pathway for Ca¢Calkyl s-bond aminolysis. Hence, no major structural reorganisation at 5·S is required. Furthermore, akin to what is found for insertive cyclisation and aminolysis steps, an effective pyrrolidine!pyrrolide conversion necessitates the coordinative stabilisation of involved key species by a metal bound spectator substrate molecule. Proton transfer evolves through a metathesis-type TS[53·S–63·(S)2] structure with an intrinsic barrier of 8.8 kcal mol¢1 to furnish bis-substrate adducted {N^N}Ca pyrrolide 63·(S)2 in a process that is virtually thermoneutral (Figure 6). Hence, 53·SQ63·(S)2 pyrrolidine!pyrrolide conversion is kinetically viable and reversible. The bis-substrate adduct 63·(S)2 is the prevalent form of the {N^N}Ca pyrrolide compound, with mono-substrate adduct 61·S and substrate-free 6 species at higher energy, well separated by 9.1 and 23.0 kcal mol¢1 (relative to 63·(S)2), respectively. The concerted proton-triggered cyclisation mechanism

Generation of the {N^N}Ca pyrrolide compound Notwithstanding that an iminoanilide alkaline-earth pyrrolide has not been identified when monitoring the process spectroscopically,[14a] it may well represent a relevant off-cycle intermediate.[11f] Thus, a detailed characterisation of viable pathways leading to its formation will undoubtedly inform our understanding of HA catalysis for the family of iminoanilide alkalineearth catalysts available. Plausible routes for generation of {N^N}Ca pyrrolide intermediate 6 have been examined, including a) pyrrolidine a-proton abstraction at {N^N}Ca amido cycloamine intermediate 5·(S)n and b) intramolecular 1,3 H-transfer at the calcium alkyl intermediate 4·(S)n, a process that may Chem. Eur. J. 2015, 21, 6765 – 6779

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This section examines the rival mechanistic scenario B in Scheme 1, which involves N¢C ring closure triggered by concomitant amino proton delivery onto the adjacent C=C linkage, thereby affording the cycloamine product through a concerted single-step transformation. For this process to be assisted by a coordinated spectator substrate molecule, the two trajectories shown in Scheme 5, which constitutes N¢C bond formation through an axial olefin approach at the Ca¢Namido sbond, provoked by a proton delivered from an equatorially bound substrate, or alternatively involving concurrent ring closure and proton transfer occurring at equatorial sites, are found to be almost indistinguishable kinetically, with the tra-

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Scheme 5. Alternative trajectories for concerted proton-triggered N¢C ring closure at bis-substrate adduct 3·(S)2 of the catalytically competent {N^N}Ae amido compound.

jectory for axial olefin approach slightly preferred (for more details, see the Supporting Information, Figures S11–S13). The concerted amidoalkene!cycloamine conversion, proceeding through the most accessible 3·S!5 and 3·(S)2 !53·S pathways shown in Figure 7, displays similar geometric features. It

tance of 1.84 æ and features disappearing N¢H (1.21 æ) and emerging C¢H (1.60 æ) bonds, all of which is indicative of a concerted but asynchronous proton transfer. The rather distinct separation between the double bond and calcium (Ca– olefin distance > 3.8 æ) indicates that N¢C bond-forming ring closure taking place outside of the immediate vicinity of the metal, thereby reflecting that amino proton delivery activates the C=C linkage and not the close interaction with the electropositive alkaline earth, as necessitated in cycle A. After traversing the TS structure, TS[3·S–5] and TS[3·(S)2–53·S] decay into the {N^N}Ca amido pyrrolidine compound 5 and its substrate adduct 53·S, respectively. The dominant 3’·(S)2 !53·S pathway for proton-assisted concerted N¢C/C¢H bond formation to evolve through a sixcentre TS structure, which appears to be only moderately susceptible to steric pressure imposed by the ligand sphere around the alkaline earth and involves a metal bound substrate molecule, has a barrier of 22.5 kcal mol¢1 to overcome and affords substrate adduct 53·S in a process that is downhill by ¢7.9 kcal mol¢1 (Figure 7). Hence, proton-assisted concerted N¢C/C¢H bond formation is irreversible as is Ca¢Calkyl s-bond aminolysis and both steps furnish 53·S. Similar to previous discussion for insertive cyclisation and aminolysis steps, an additionally coordinated spectator substrate molecule serves profoundly in stabilising involved key species.

Comparison of mechanistic pathways

Figure 7. Most accessible pathways for N¢C bond formation with concurrent delivery of the amino proton to the olefin unit at the [{N^N}Ca(NHR)] compound with one 3·S (top) or two 3·(S)2 (bottom) coordinated substrate molecules.[19, 20b]

evolves through a six-centre TS structure that constitutes N¢C5 bond-forming ring closure with concomitant transfer of a calcium bound, and hence, acidified substrate molecule on the adjacent olefin-C6 centre. As exemplified in Figure 8 for the trajectory of axial olefin approach with a spectator substrate molecule involved, the located TS[3·(S)2–53·S] occurs at a N¢C5 dis-

Figure 8. Selected structural parameter (æ) of the located TS structure for proton-assisted concerted N¢C/C¢H bond formation at 3·(S)2 via a trajectory for axial olefin approach.[21] Chem. Eur. J. 2015, 21, 6765 – 6779

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Having completed the exploration of relevant elementary steps for alternative cycles A and B in Scheme 1, Figure 9 collates the free-energy profiles assessed for the two mechanistic scenarios for cyclohydroamination of aminoalkene S in the presence of a catalytically competent iminoanilide [{N^N}Ca(NHR)·(NH2R)2] amido compound. It focuses on the most accessible pathways only, whereas other energetically prohibitive or less probable pathways have been omitted. It is worth nothing that the thermodynamic driving force for S!P cyclisation has been subtracted from 5·S, 6·(S)2 and TS[5·S–6·(S)2]. Figure 9 reveals that the three conceivable candidates for the catalyst resting state, {N^N}Ca amidoalkene 3·(S)2, {N^N}Ca amido cycloamine 53·S and {N^N}Ca pyrrolido 63·(S)2, the various possible conformers of which are expected to participate in rapid equilibria,[19] are remarkably similar in free energy, with 3·(S)2 somewhat favoured. However, the 3·(S)2 + HN(SiMe3)2Q2·(S)2 + S substitution of the amidoalkene for a silylamido unit is an equilibrium that lies well toward the right (DG = ¢4.9 kcal mol¢1; see Catalyst initiation section). DFT predicts the {N^N}Ca silylamido bis-substrate adduct 2·(S)2 to be the most stable species that is readily accessible and thus likely corresponds to the catalyst resting state. It is readily converted into the catalytically competent calcium amidoalkene compound, which is predominantly present as bis-substrate adducts (3·(S)2, 3’·(S)2). The assessed thermodynamic gap between 2·(S)2 and 3·(S)2, 53·S and 63·(S)2 limits their population available under catalytic conditions and renders those intermediates rather unlikely to be observable by spectroscopy.

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Figure 9. Condensed reaction profile for intramolecular hydroamination of aminoalkene S (S 1) by an iminoanilide {N^N}Ca amido catalyst proceeding through alternative mechanistic cycles.[22] The pyrrolidineQpyrrolide conversion is included. ({N^N}¢ = [ArN(o-C6H4)C(H)=NAr]¢ with Ar = 2,6-iPr2C6H3).

The N¢C bond-forming ring closure with concurrent amino proton transfer to proceed outside of the immediate vicinity of the electropositive calcium centre through a six-centre TS[32’·(S)2–53·S] structure is irreversible and has a total barrier of 27.4 kcal mol¢1 (relative to the 2·(S)2 catalyst resting state) to overcome. The observed substantial primary KIE is easily explained by this concerted pathway, but the stepwise s-insertive pathway shown in Figure 9 is equally consistent. This pathway entails 1) facile and reversible 33’·(S)2Q43·(S)2 insertive N¢C s-bond-forming cyclisation that favours the {N^N}Ca amidoalkene catalyst species; 2) downhill turnover-limiting 43·(S)2 ! 53·S Ca¢Calkyl s-bond aminolysis at the transient {N^N}Ca alkyl intermediate; followed by 3) kinetically facile displacement of the cycloamine by incoming substrate to regenerate the {N^N}Ca amidoalkene active catalyst complex. The two mechanistic cycles account equally well for all of the observed key process features, display a thermodynamic force of identical magnitude and are, moreover, indistinguishable by an empirical rate law. The proton-assisted concerted N¢ C/C¢H bond-forming pathway is seen to be energetically prohibitive in the presence of a kinetically less demanding s-insertive pathway. The magnitude of the assessed kinetic disparity (DDG = 8.0 kcal mol¢1; Figure 9) lets one confidently conclude that the s-insertive pathway is exclusively traversed. The assessed total barrier of 19.4 kcal mol¢1 (relative to the 2·(S)2 catalyst resting state) for turnover-limiting calcium–alkyl s-bond aminolysis matches the empirically determined Eyring parameter (DG = 19.4 2.1 kcal mol¢1 (298 K))[14] gratifyingly well. Chem. Eur. J. 2015, 21, 6765 – 6779

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In light of all these aspects, the herein-presented computational mechanistic analysis provides compelling evidence for the operation of a stepwise s-insertive pathway for aminoalkene HA in the presence of a catalytically competent iminoanilide calcium amido compound.

Comparison of [{N^N}Ae(NHR)]-mediated HA of aminoalkene S (Ae = Ca, Sr, Ba) Catalyst initiation In the [{N^N}Ae{N(SiMe3)2}·(thf)n] starting material, the number of coordinated THF molecules predicted by the employed DFT methodology [Ae = Ca (n = 1), Sr (n = 2), Ba (n = 2)] gratifyingly matches experiment. The conversion of the starting material sees an initial displacement of THF by the aminoalkene substrate, leading to bis-amine-coordinated Ae¢2·(S)2 as the prevalent encounter complex. As shown in Figure 10, the calcium silylamide binds the primary amine S most strongly, with Ae¢ amine/amido bond strengths regularly diminished for less compact alkaline earths. The conversion of the Ae silylamide into the Ae amidoalkene catalyst compound is kinetically feasible in each case and is facilitated across the series Ba < Sr < Ca on both kinetic and thermodynamic grounds. Interestingly, the forward barrier for protonolytic Ae¢N s-bond cleavage (DG = 14.0/14.3/16.9 kcal mol¢1 for Ca/Sr/Ba) is of similar magnitude for calcium and strontium, whereas amine/silylamide transamination is expected to be slowed down for barium. The as-

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Figure 10. Ae¢Namido s-bond aminolysis at Ae¢2 by substrate S (Ae = Ca/Sr/Ba).[19, 20a,c]

sessed thermodynamic gap between 2·(S)2 and 3·(S)2 (DG = 4.9/6.7/9.0 kcal mol¢1 for Ca/Sr/Ba), which is found to increase regularly for heavier alkaline earths, is indicative that the kinetically sufficiently rapid 2·(S)2Q3·(S)2 equilibrium lies well towards the 2·(S)2 catalyst resting state for all three alkaline earths, the more so for heavier analogues. Moreover, the strength of the Ae¢amido s-bond in the 2·(S)2 silylamide resting state and the 3·(S)2 amidoalkene catalyst compound increases regularly for increasingly more compact alkaline earths. The tendency to form amido-bridged dimers has also been studied as a factor that affects the availability of catalytically competent monomeric Ae amidoalkene species. The substratefree 3ad dimer, which is preferred for calcium, and substrate adduct 3ad·S, as the predominantly generated dimer species for barium, are seen to be modestly more stable than 3’·S, but association of another substrate molecule proves to be more effective for stabilising the {N^N}Ae amidoalkene catalyst compound. Overall, the kinetically sufficiently active 2·(S)2Q3·(S)2 transaminative equilibrium, which lies well toward the Ae silylamide resting state (with the thermodynamic gap widening in the order Ca < Sr < Ba) limits the population of catalytically competent {N^N}Ae amidoalkene species able to effect catalyst turnover. Hence, in neither of the iminoanilide alkaline-earth amido catalyst systems is a [{N^N}Ae(NHR)] compound likely to be observed spectroscopically.

The s-insertive mechanism Migratory olefin 1,2-insertion into the Ae¢Namido s-bond via the most accessible 33’·(S)2Q43·(S)2 pathway, which involves two coordinated spectator substrate molecules, is found to be similarly kinetically facile for calcium and strontium, but somewhat more demanding kinetically for barium (DG = 9.3/8.9/12.0 kcal mol¢1 for Ca/Sr/Ba, relative to 33’·(S)2 ; Figure 11). When taking into account the energy cost required for structural reorganisation within the amidoalkene manifold to position the olefin unit favourably proximal to the alkaline earth and cis to the Ae¢Namido s-bond (i.e., the energy gap associated to 3·(S)2Q33’·(S)2), strontium appears to be most effective in facilitating insertive cyclisation kinetically, with barriers in the order Ca Sr < Ba. However, reversible 33’·(S)2Q43·(S)2 cyclisation becomes less favourable thermodynamically for the heavier alkaline-earth analogues, which follows a regular Ca > Sr > Ba trend. The insertive cyclisation step is favoured kinetically and thermodynamically by several factors; most importantly, the more effective activation of the double bond against a nucleophilic Ae¢Namido attack together with an absence of noticeable protection of the alkaline earth for an approaching olefin unit (as exemplified by the relative stabilities for Ae¢33’·(S)2) for more compact group 2 elements (this despite the stronger Ae¢amido s-bond). The smaller Ae¢N s-bond polarity and the limited polarisability of the more compact calcium and stronti-

Figure 11. Most accessible pathways for migratory olefin 1,2-insertion into the Ae¢Namido s-bond at substrate adduct Ae¢3’·(S)2 followed by Ae¢C s-bond aminolysis at the {N^N}Ae alkyl intermediate (Ae = Ca/Sr/Ba).[19, 20b,c] Chem. Eur. J. 2015, 21, 6765 – 6779

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Full Paper um ions, however, appear to be of less importance, as they would rather contradict the predicted reactivity trend. Subsequent Ae¢Calkyl s-bond aminolysis, which is turnoverlimiting for all three catalyst systems, is found to also follow a regular but opposite Ca < Sr < Ba trend as far as the innate reactivity is concerned (DG = 7.3/6.5/6.0 kcal mol¢1 relative to 43·(S)2 ; Figure 11) and is most efficient for the heaviest barium analogue on both kinetic and thermodynamic grounds. This trend, which may seemingly be at odds with the observed superiority of the {N^N}Ca amido catalyst system in effecting aminoalkene HA catalysis, indicates that among the counteracting effects of diminishing amine N¢H acidity and increased Ae¢C s-bond polarity upon going down group 2 the Ae¢alkyl s-bond strength prevails, such that the less strong Ba–alkyl bond facilitates Ae¢C s-bond aminolysis when compared with its lighter analogues. However, a realistic view of the catalytic abilities of iminoanilide alkaline-earth catalysts requires the following factors to be taken into account; 1) 3·(S)2Q33’·(S)2Q43·(S)2 insertive cyclisation and 2) 3·(S)2 + HN(SiMe3)2Q2·(S)2 + S transamination. Although of the effectiveness of barium in facilitating Ae¢C azacycle tether s-bond cleavage, the profound thermodynamic penalty imposed on insertive cyclisation, thereby giving rise to a relatively high-energy {N^N}Ba alkyl intermediate, render it least efficient (DG = 14.5/14.8/16.8 kcal mol¢1 for Ca/Sr/Ba, relative to the prevalent catalytically competent 3·(S)2 species, Figure 11) when compared to its more compact analogues. Moreover, taking the transaminative aminoalkene/silylamine pre-equilibrium into account, which limits the population of [{N^N}Ae(NHR)] species available for catalyst turnover regularly for increasingly more heavier alkaline earths (Figure 10), the resulting total barrier of 19.4/21.5/25.8 kcal mol¢1 (for Ca/Sr/Ba, relative to the 2·(S)2 resting state) for turnover-limiting protonolysis matches observed reactivity trends and estimated Eyring data[14c] remarkably well.[23]

The concerted proton-triggered cyclisation mechanism Aiming to further enhance our understanding of structure-reactivity relationships, Figure 12 collates the energy profile for the most accessible pathway for concerted proton-triggered cyclisation. For all the [{N^N}Ae(NHR)] catalysts the proton-assisted concerted N¢C/C¢H bond formation proceeding via the dominant 3·(S)2 !53·S pathway is found energetically non-competitive with the operative s-insertive mechanism. Steric protection of the metal centre for the olefin unit is likely to in-

Figure 12. Most accessible pathways for N¢C bond formation with concurrent delivery of the amino proton to the olefin unit at the [{N^N}Ae(NHR)] compound with two coordinated substrate molecules (Ae = Ca/Sr/Ba).[19, 20b,c] Chem. Eur. J. 2015, 21, 6765 – 6779

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crease the energy demands for insertive cyclisation on both kinetic and thermodynamic grounds and hence may slow down the stepwise s-insertive mechanistic pathway. Given that activation of the olefin unit does not require a close interaction with the electropositive alkaline earth, the concerted protonassisted mechanism that evolves through a sterically less-demanding multi-centre TS structure (see Figure 8) may become favourable under such circumstances. The small energy gap between 3·(S)2 and 3’·(S)2 (exemplified in Figure 11 for 33’·(S)2) indicates that in neither case the alkaline earth becomes unapproachable for the aminoalkene unit by a moderately sterically encumbering {N^N}Ae ligation. It finds further manifestation in the assessed magnitude of the kinetic gap between TS[43·(S)2– 53·S] and TS[3·(S)2–53·S], which discriminates between rival mechanistic pathways. As a result of a similarly approachable alkaline earth, the largest gap of 8.0 kcal mol¢1 is predicted for calcium, whereas the gap narrows somewhat to 6.2 (Sr) and 6.9 kcal mol¢1 (Ba) for the heavier analogues (Figures 11 and 12). If one wishes to pursue the idea of favouring the concerted over the stepwise cyclisation pathway by imposing severe steric demands at the {N^N}Ae backbone, this is thus unlikely to succeed in the quest for ever more efficient group 2 metal HA catalysts.

Comparison with [{N^N}Ae(NR2)]-mediated intermolecular HA (Ae = Ca, Sr, Ba) The family of iminoanilide alkaline-earth silylamido compounds 2 (Ae = Ca, Sr, Ba) have also been reported to competently mediate intermolecular alkene hydrofunctionalisation and to display exceptionally high activities for the HA of styrene with reaction rates increasing across the series Ca < Sr < Ba.[15] Computational mechanistic analysis of HA of styrene with pyrrolidine by 2 revealed that after the initial conversion of 2 into the catalytically competent alkaline-earth pyrrolide compound the process proceeds with strict 2,1-regioselectivity through a s-insertive pathway, whereas a rival concerted proton-assisted insertion mechanism, which bears some similarity with the concerted pathway characterised before, was found to be kinetically non-competitive.[15b] The reversal of trends in reactivity observed in intramolecular (Ca > Sr > Ba) and intermolecular (Ca < Sr < Ba) HA by iminoanilide alkaline-earth catalysts is intriguing. The reasons behind it, however, have remained elusive thus far. Accessibility of the alkaline earth is, among others, a prime factor that determines the catalytic performance. As far as cyclohydroamination is concerned, the metal centre appears not to be protected against an approach of the amidoalkene unit in either case and, moreover, all the alkaline earths appear to be approachable to a similar extent (see above). Hence, its more effective interaction with a more compact alkaline-earth centre, which favours insertive cyclisation on both kinetic and thermodynamic grounds, together with a sufficiently facile Ae¢C azacycle tether s-bond aminolysis and an energetically more balanced transaminative pre-equilibrium, render calcium the most efficient in cyclohydroamination catalysis, with barium the least efficient.

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Full Paper The situation appears to be different for intermolecular HA.[15b] The association of styrene at the bis-amine-coordinated {N^N}Ae pyrrolide resting state I3·(A)2 (A = pyrrolidine) to afford the catalytically competent species I3·St·(A)2 (St = styrene) that participates in the most accessible pathway for migratory olefin 2,1-insertion is seen to be more demanding energetically than formation of 3’·(S)2 featuring a chelating amidoalkene due to increased entropy costs, but also due to enhanced steric demands. The styrene association is more unfavourable the more compact the alkaline earth becomes, as indicated by a thermodynamic gap between I3·(A)2 and I3·St·(A)2 (Figure 13) that widens substantially across the series Ca > Sr > Ba. As analysed previously in great detail,[15b] limitations in accessibility, together with a strengthened Ae¢pyrrolido s-bond for lighter alkaline earths, are major factors that render olefin insertion less favourable on both kinetic and thermodynamic grounds. Given that subsequent Ae¢C s-bond aminolysis features an almost identical intrinsic barrier, it ultimately gives rise to a poorer performance for strontium and calcium when compared to the best-performing barium catalyst.

Conclusion The present study aims to contribute towards a more detailed understanding of mechanistic intricacies and catalytic structure-reactivity relationships of alkaline-earth-mediated HA of aminoalkenes. It employs DFT as an established and predictive method to scrutinise rival mechanistic pathways for cyclohydroamination of prototype 2,2’-dimethylpent-4-en-1-amine by kinetically stabilised iminoanilide [{N^N}Ae{N(SiMe3)2}·(thf)n] alkaline-earth precatalysts (Ae = Ca, Sr, Ba; {N^N}¢ = [ArN(oC6H4)C(H)=NAr]¢ with Ar = 2,6-iPr2C6H3). Two plausible mechanistic avenues are equally consistent with an empirically derived second-order rate law and observed significant primary KIEs. Firstly, a single-step amidoalkene!cycloamine conversion through a concerted proton-assisted N¢C/C¢H bond formation proceeding outside of the immediate vicinity of the electropositive alkaline earth and, secondly, a stepwise s-insertive pathway that involves a fast and reversible migratory olefin 1,2-insertion into the Ae¢Namido s-bond linked to irreversible

and less rapid Ae¢C azacycle tether s-bond aminolysis. The computational examination presented herein reveals non-competitive kinetic demands for a pathway describing N¢C ring closure triggered by concurrent amino proton delivery at the C=C linkage evolving through a multi-centre TS structure, which militates against the operation of a concerted proton-assisted cyclisation pathway. The prevailing stepwise s-insertive mechanism sees the initial conversion of the bis-amine-coordinated {N^N}Ae silylamido catalyst resting state 2·(S)2 into the catalytically competent {N^N}Ae amidoalkene compound (to be predominantly present as 3·(S)2, 3’·(S)2) and entails thereafter the following steps: 1) Facile and reversible 33’·(S)2Q43·(S)2 insertive N¢C s-bond-forming cyclisation that favours the {N^N}Ae amidoalkene catalyst species; 2) downhill turnover-limiting 43·(S)2 !53·S Ae¢C s-bond aminolysis at the transient {N^N}Ae alkyl intermediate; 3) kinetically easy displacement of the cycloamine by incoming substrate to regenerate the {N^N}Ae amidoalkene active catalyst complex. The DFT-derived effective barrier matches the empirically determined Eyring parameter gratifyingly well[14] and correctly predicts the decrease in rate observed across the series Ca > Sr > Ba. The detailed analysis of relevant steps for [{N^N}Ae(NHR)] catalysts reveals that the aptitude for olefin approach at the catalytically competent {N^N}Ae amidoalkene compound is of similar magnitude. Hence, in the absence of substantial steric protection of the alkaline earth, the more effective interaction of the double bond with a more compact alkaline-earth centre favours insertive cyclisation on both kinetic and thermodynamic grounds. This behaviour, together with a sufficiently facile Ae¢C azacycle tether s-bond aminolysis and an energetically more balanced transaminative pre-equilibrium, render calcium the most and barium the least efficient in cyclohydroamination catalysis. Moreover, the factors responsible for the reverse trends in reactivity observed in intermolecular (Ca < Sr < Ba) and intramolecular (Ca > Sr > Ba) HA catalysis for the studied family of iminoanilide alkaline-earth catalysts have been rationalised. The invaluable insights into catalytic structure-reactivity relationships reported herein will likely direct the rational design of alkaline-earth-based HA catalysts.

Figure 13. Most accessible pathways traversed in HA of styrene with pyrrolidine comprising migratory olefin 2,1-insertion into the Ae¢N pyrrolido s-bond at Ae¢I3·St·(A)2 followed by Ae¢C s-bond aminolysis at the {N^N}Ae alkyl intermediate (Ae = Ca/Sr/Ba). Chem. Eur. J. 2015, 21, 6765 – 6779

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Full Paper Computational Methodology All calculations based on Kohn–Sham density functional theory (DFT)[24] were performed by means of the program package TURBOMOLE[25] employing flexible basis sets of triple-z quality. The Becke–Perdew (BP86)[26] generalised gradient approximation (GGA) functional within the RI-J integral approximation[27] in conjunction with appropriate auxiliary basis sets was used for structure optimisation. Empirical dispersion corrections by Grimme (D3 with Becke–Johnson damping)[28] were used to account for critical noncovalent interactions involved in the studied HA catalysis. For alkali-earth metals we used the Stuttgart–Dresden scalar-relativistic effective core potential (SDD, 46 and 28 core electrons for Ba and Sr, respectively)[29] in combination with the (7s7p5d1f)/[6s4p3d1f] (def2-TZVPP) valence basis set,[30] whereas calcium was treated by the (17s12p4d)/[6s5p3d] (def2-TZVPP) all-electron basis set.[30] All remaining elements were represented by Ahlrich’s valence triple-z TZVP basis set[31a,b] with polarisation functions on all atoms. Final electronic energies were obtained from single-point calculations at BP86-D3 optimised structures using the B97-D[32] GGA functional (together with D3(BJ) empirical dispersion correction)[28] in conjunction with the aforementioned ECP/basis set for alkaline earths and a def2-TZVP basis set[30] for all remaining elements (B97-D3/(SDD + def2-TZVP)//BP86-D3/(SDD + TZVP)). The validity of the computational protocol employed for reliably mapping the energy landscape of alkaline-earth-mediated hydroamination has been substantiated before[15b] and this allowed mechanistic conclusions with substantial predictive value to be drawn. The free-energy landscape of the entire HA course was derived for the prototype 2,2’-dimethylpent-4-en-1-amine substrate (S 1) together with iminoanilide [{N^N}Ae{N(SiMe3)2}·(thf)n] alkaline-earth silylamido precatalysts 2 (Ae = Ca, Sr, Ba; {N^N}¢ = [ArN(oC6H4)C(H)=NAr]¢ with Ar = 2,6-iPr2C6H3). No structural simplification of any of the key species involved was imposed. The DFT calculations have simulated the authentic reaction conditions by treating the bulk effects of the benzene solvent by a consistent continuum model in form of the conductor-like screening model for realistic solvents (COSMO-RS).[33] This solvation model includes continuum electrostatic and also solvent-cavitation and solute-solvent dispersion effects through surface-proportional terms. The free solvation enthalpy has been assessed with the aid of COSMO-RS at the BP86[26]/(SDD + def2-TZVPD)//BP86-D3/(SDD + TZVP)[29–31] level of approximation. Geometry optimisation and frequency calculations were performed at the BP86-D3/(SDD + SV(P))[31c] level to confirm the nature of all optimised key structures and to determine thermodynamic parameters (298 K, 1 atm) under the conventional ideal-gas, rigid-rotor and quantum-mechanical harmonic-oscillator approximation. The entropy contributions for condensed-phase conditions were estimated based on computed gas-phase entropies by employing the procedure of Okuno.[34] The mechanistic conclusions drawn in this study were based on the Gibbs freeenergy profile of the entire catalytic cycle assessed at the B97D3(COSMO-RS)/(SDD + def2-TZVP) level of approximation for experimental condensed phase conditions. Calculated structures were visualised by employing the StrukEd program,[35] which was also used for the preparation of 3D molecule drawings.

Keywords: alkaline-earth metals · density functional calculations · homogeneous catalysis · hydroamination · reaction mechanisms [1] For reviews of catalytic hydroamination, see: a) L. S. Hegedus, Angew. Chem. Int. Ed. 1998, 37, 1113; Angew. Chem. 1988, 100, 1147; b) D. M. Chem. Eur. J. 2015, 21, 6765 – 6779

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Roundhill, Catal. Today 1997, 37, 155; c) T. E. Mìller, M. Beller, Chem. Rev. 1998, 98, 675; d) M. Nobis, B. Drießen-Hçlscher, Angew. Chem. Int. Ed. 2001, 40, 3983; Angew. Chem. 2001, 113, 4105; e) R. Taube in Applied Homogeneous Catalysis with Organometallic Complexes (Eds.: B. Cornils, W. A. Herrmann), Wiley-VCH, Weinheim, 2002, pp. 513 – 524; f) F. Seayad, A. Tillack, C. G. Hartung, M. Beller, Adv. Synth. Catal. 2002, 344, 795; g) G. A. Molander, J. A. C. Romero, Chem. Rev. 2002, 102, 2161; h) F. Pohlki, S. Doye, Chem. Soc. Rev. 2003, 32, 104; i) P. W. Roesky, T. E. Mìller, Angew. Chem. Int. Ed. 2003, 42, 2708; Angew. Chem. 2003, 115, 2812; j) J. F. Hartwig, Pure Appl. Chem. 2004, 76, 507; k) S. Hong, T. J. Marks, Acc. Chem. Res. 2004, 37, 673; l) K. C. Hultzsch, Adv. Synth. Catal. 2005, 347, 367; m) A. L. Odom, Dalton Trans. 2005, 225; n) R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36, 1407; o) I. Aillaud, J. Collin, J. Hannedouche, E. Schulz, Dalton Trans. 2007, 5105; p) J. F. Hartwig, Nature 2008, 455, 314; q) T. E. Mìller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev. 2008, 108, 3795; r) S. Doye in Science of Synthesis, Vol. 40a (Eds.: M. Christmann, E. Schaumann, D. Enders), Thieme, Stuttgart, 2009, pp. 241 – 304; s) P. S. Hanley, J. F. Hartwig, Angew. Chem. Int. Ed. 2013, 52, 8510; Angew. Chem. 2013, 125, 8668. [2] For cyclohydroamination mediated by organolanthanides, see: a) M. R. Gagne, T. J. Marks, J. Am. Chem. Soc. 1989, 111, 4108; b) M. R. Gagne, T. J. Marks, J. Am. Chem. Soc. 1992, 114, 275; c) Y. Li, P.-F. Fu, T. J. Marks, Organometallics 1994, 13, 439; d) Y. Li, T. J. Marks, J. Am. Chem. Soc. 1996, 118, 9295; e) G. A. Molander, E. D. Dowdy, J. Org. Chem. 1998, 63, 8983; f) M. R. Bìrgstein, H. Berberich, P. W. Roesky, Organometallics 1998, 17, 1452; g) V. M. Arredondo, F. E. McDonald, T. J. Marks, Organometallics 1999, 18, 1949; h) A. T. Gilbert, B. L. Davis, T. J. Emge, R. D. Broene, Organometallics 1999, 18, 2125; i) G. A. 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