CuH-mediated Hydroamination of Styrene

CuH-mediated Hydroamination of Styrene Abstract: A detailed computational exploration of mechanistic intricacies of the copper(I) hydride (CuH)-catalysed hydroamination of styrene with a prototype hydoxylamine ester by a recently reported (dppbz)CuH catalyst (dppbz ≠¡ {P^P} ≠¡ 1,2-bis(diphenylphosphino)benzene) is presented. A variety of plausible mechanistic avenues have been pursued by means of a sophisticated computational methodology, from which a general understanding of the factors controlling hydroamination catalysis emerged. The catalytically competent {P^P}CuI hydride, which is predominantly present as its dimer, involves in irreversible hydrocupration proceeding with complete 2,1 regioselectivity to form a secondary {P^P}CuI benzyl intermediate. Its interception with benzylamine ester produces the branched tertiary amine product and {P^P}CuI benzoate upon intramolecular SN2 disruption of the amine electrophiles N-O linkage to precede highly rapid, strongly exergonic C-N bond-forming reductive eliminati on. The {P^P}CuI benzoate corresponds to the catalyst resting state and its conversion back into the {P^P}CuI hydride upon transmetalation with a hydrosilane is turnover limiting. The effect of electronic perturbations at the amine electrophile upon the reaction rate for productive hydroamination catalysis and also non-productive reduction of the hydroxylamine ester has been gauged, which unveiled a more fundamental insight into catalytic structure-performance relationships. Introduction The catalytic hydroamination (HA) reaction, the direct addition of an N-H bond across an unsaturated carbon-carbon linkage, offers facile access to an industrially relevant organonitrogen commodity and fine chemicals in a green, waste-free and highly atom-efficient manner.[1] By focusing on late d-block metal catalysis, several distinct mechanistic pathways have been revealed over the years for the hydroamination of alkenes, including the following principal processes: 1) N-H bond activation with subsequent alkene insertion into the metal-NR2 linkage,[2] nucleophilic attack of an amine at a metal-bound alkene,[3] nucleophilic attack of a metal amido species at an activated alkene[4] and amine coordination to be followed by proton transfer onto an activated alkene.[5] Despite the significant progress achieved over the past years the utilisation of these methodologies is still limited by a number of drawbacks.[1] The development of a general approach for regio- and enantioselective hyd roamination of a broad range of alkene substrate classes, in particular, remains an important challenge in the context of intermolecular HA. Recently, the groups of Miura[6] and Buchwald[7a] reported independently a mechanistically distinct approach for styrene HA that involves copper(I) hydride (CuH) as the catalyst together with amine electrophiles and a hydrosilane hydride source to furnish amines in excellent yields and enantio-/regioselectivities under mild conditions.[8] Miura and co-workers disclosed that styrenes react with benzylamine ester reagents in THF at room temperature to afford exclusively branched benzylic tertiary amines in the presence of a (dppbz)CuH catalyst (dppbz ≠¡ {P^P} ≠¡ 1,2-bis(diphenylphosphino)benzene) and a hydrosilane hydride source (Scheme 1).[6] Treatment of the Cu(OAc)2/dppbz starting material with Li(OtBu) and a reducing agent likely gives rise to {P^P}Cu(OtBu) 2, which becomes converted into the catalytically competent {P^P}CuI hydride 3 through transmetalation with silane. According to plausible mechanistic pathways outlined in Scheme 2 styrene insertion into the Cu-H linkage at 3 leads to {P^P}CuI alkyl 4 that couples with the benzylamine ester electrophile thereafter to generate amine product P and {P^P}CuI benzoate 6. Various mechanistic pathways can be envisaged for this transformation,[9] but its precise details remain largely elusive thus far. Transmetalation of 6 with hydrosilane regenerates the catalytically competent {P^P}CuI hydride for another catalyst turnover. The performance of HA catalysis via the productive cycle can be compromised by the well known aptitude of the {P^P}CuI hydride to reduce the amine electrophile. This may proceed through various pathways to involve formation of either N-H (one plausible path via a {P^P}CuIII benzoate amido hydride intermediate 7 is exemplified in Scheme 2) or O-H bonds to afford {P^P}CuI benzoate 6 by consumption of a molar equivalent of the amine electrophile. Precise knowledge of both the operative mechanism and of catalytic structure-performance relationships are indispensable for the rational design of improved HA catalysts. In light of the fact that precise details of mechanistic intricacies of CuH-mediated vinylarene HA remain largely elusive thus far,[10] a sophisticated computational protocol has been employed as an established and predictive means to study reaction mechanisms and to guide rational catalyst design. The present study scrutinises rival mechanistic pathways for HA of styrene (1a ≠¡ S) with O-benzoyl-N,N-dimethyl-hydroxylamine (1b ≠¡ A) by a catalytically competent dppbz-ligated CuI hydride complex in the presence of prototype trimethylsilane (1c ≠¡ H) as hydride source. No structural simplification (other than replacing O-benzoyl-N,N-diethyl-hydroxylamine and HSiPh3 used in experiment by 1b and 1c, respectively, solely for the purpose of computational efficiency) of any kind has been imposed for any of t he key species involved. The computational methodology employed (highly accurate DLPNO-CCSD(T) in conjunction with basis sets of def2-TZVP quality and a sound treatment of bulk solvent effects) simulated authentic reaction conditions adequately and mechanistic analysis is based on Gibbs free-energy profiles. This computational protocol can confidently be expected to reliably map the energy landscape and this has allowed mechanistic conclusions with substantial predictive value to be drawn. As detailed herein, our comprehensive mechanistic examination provides support that effective HA catalysis involves irreversible hydrocupration with strict 2,1 regioselectivity to be followed by generation of the branched tertiary amine product by interception of the thus formed secondary {P^P}CuI benzyl nucleophile with amine electrophile. The prevailing pathway sees the first intramolecular SN2 displacement of the benzoate leaving group and is followed by highly facile and strongly exergonic C-N bond-generating reductive elimination from a highly reactive, intervening {P^P}CuIII species. It leads to amine product and {P^P}CuI benzoate, the latter of which corresponds to the catalyst resting state. Its conversion back into the catalytically competent {P^P}CuI hydride is turnover limiting. Results and Discussion The aim of the present study is twofold. A first part scrutinises thoroughly all the relevant elementary steps of Scheme 2, with special attention devoted to the several mechanistic avenues that can be invoked regarding the interaction of {P^P}CuI alkyl nucleophile with the amine electrophile and also the productivity-limiting reduction of the amine transfer agent. A second part explores the effect of electronic perturbations at the amine electrophile upon catalyst performance. {P^P}CuH-mediated HA of styrene with amine electrophile 1b Catalyst initiation Effective HA catalysis entails the initial conversion of {P^P}Cu(OtBu) 2 into the catalytically competent {P^P}CuI hydride compound. The ability of hydrosilane 1c (≠¡ H) to affect transmetalation at 2, although being rather unlikely turnover limiting, will influence the performance of HA catalysis, since it determines the amount of catalytically competent {P^P}CuI hydride species available for catalyst turnover. Hydroxylamine ester 1b (displaying a slight preference for à ¯Ã‚ Ã‚ «1-N over à ¯Ã‚ Ã‚ «1-O donor ligation) and THF (T) show a comparable aptitude to bind at copper in 2. However, the entropic costs linked with reactant association place the respective adducts 2†¢A, 2†¢T higher in free energy relative to the separated fragments. This gap widens regularly for ever weaker donor molecules as clearly seen in Figure 1 for silane (2†¢H) adducted species. Furthermore, 2 exhibits no propensity toward dimer formation, as all the efforts to localise a dimeric species failed. After the initial facile, but uphill association of trimethylsilane 1c at 2, transmetalation evolves through a metathesis-type transition-state (TS) structure (see Figure S1 in the Supporting Information), which decays thereafter into the {P^P}CuI hydride complex 3 through facile liberation of Me3SiOtBu. Figure 2 reveals an affordable kinetic barrier (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 22.4 kcal mol-1 relative to {2 + 1c}) for conversion of 2 into the catalytically competent complex 3, which is driven by a thermodynamic force of substantial amount. {P^P}CuI hydride compound Reactant (styrene S, hydroxylamine ester A, hydrosilane H), amine product (P) and THF (T) solvent molecules can associate in various ways at copper in the catalytically competent hydride compound (see Figure S2 in the Supporting Information) to give rise to a multitude of adducted species, all of which are expected to participate in mobile association/dissociation equilibria.[11] Similar to what is found for 2, the copper centre can accommodate only a single molecule;[13] its moderate binding enthalpy, however, cannot compensate for the associated entropic costs, thereby rending the various adducted species to be higher in free energy than the respective separated fragments. Amines (A, P) and styrene (benefitting from coppers ability for backbonding) are found to associate preferably and hence 3†¢A, 3†¢S display an energy gap (relative to separated fragments) that is somewhat smaller than for 3†¢T and 3†¢H (Figure 3). On the other hand, 3 exhibits a pronounced pro pensity towards dimer formation with 3dim is favoured by 7.5 kcal mol-1 relative to 3 (Figure 3). Hence, the catalytically competent {P^P}CuI hydride is predominantly present as dimer 3dim with relevant adducts 3†¢S (productive cycle, Scheme 2) and 3†¢A (non-productive cycle, Scheme 2) are well separated and higher in free energy by more than 12 kcal mol-1 (Figure 3). Styrene insertion into the Cu-H linkage Following the plausible catalytic scenario in Scheme 2, the productive cycle entails the first generation of {P^P}CuI alkyl 4. Alternative regioisomeric pathways for migratory C=C bond insertion into the Cu-H à ¯Ã‚ Ã‚ ³-bond commencing from 3†¢S have been examined. The possible participation of another reactant, amine product or solvent molecule has been probed explicitly, but neither encounter, product or TS structures featuring a stable coordination of a spectator molecule could be located.[13] Common to both pathways for 1,2 and 2,1 insertion is the evolution of C-H bond formation through a four-centre planar TS structure describing metal-mediated migratory insertion of the styrene C=C linkage into the polar Cu-H bond, which occurs at distances of 1.57-1.65 Ã… (see Figure S3 in the Supporting Information) for the emerging C-H bond. Following the reaction path further, TS structures decay into primary {P^P}CuI alkyl 4b (1,2 insertion) and secondary {P^P}CuI benzyl 4a (2,1 insertion), respectively. Effective delocalisation of electron density is known to markedly influence the stability of the polarised TS structure describing the interaction of an electron-rich Cu-H à ¯Ã‚ Ã‚ ³-bond with the styrene C=C linkage and also of 4, such that the regioselectivity of the hydrocupration is largely dictated on electronic grounds.[14] The  °-electron-withdrawing arene functionality at the styrene carbon directly adjacent to the copper centre effects an effective depletion of electron density from the nonsubstituted olefinic CH2 centre in the TS structure and also assist through hyperconjugative interaction with the stability of 4a. Hence it electronically stabilises both the TS structure for 2,1 insertion and 4a when compared to the species involved in 1,2 insertion that are devoid of such an opportunity. The located TS and product species (see Figure S3 in the Supporting Information) give no indication that the electronic predisposition towards 2,1 insertion is likely to be reversed due to favourable {P^P}Cu-arene interactions along the 1,2 pathway. Thus, 2,1 insertion is expected to prevail energetically on both kinetic and thermodynamic grounds. Indeed, Figure 4 reveals that migratory olefin insertion proceeds with complete 2,1 regioselectivity to afford secondary {P^P}CuI benzyl 4a by overcoming a barrier of 21.6 kcal mol-1 (à ¯Ã‚ Ã¢â‚¬Å¾G relative to 3dim), whereas the 1,2 pathway remains inaccessible due to higher kinetic demands (à ¯Ã‚ Ã¢â‚¬Å¾Ãƒ ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 4.1 kcal mol-1) and is also disfavoured thermodynamically (à ¯Ã‚ Ã¢â‚¬Å¾Ãƒ ¯Ã‚ Ã¢â‚¬Å¾G = 4.4 kcal mol-1). It characterises hydrocupration via the energetically prevalent 2,1 pathway to be kinetically viable and irreversible.[15] Amine product generation upon interception of 4 by amine electrophile The interception of {P^P}CuI alkyl 4 with amine electrophile 1b gives rise to the generation of amine product P and releases {P^P}CuI benzoate 6 (Scheme 2). Various mechanistic scenarios are conceivable for this transformation,[9] but, unfortunately, virtually no precise details of the operative mechanism are available.[10] This section intends to fill this gap by thoroughly examining several rival pathways. It includes the cleavage of the hydroxylamine ester N-O linkage via: 1) SN2 displacement of the benzoate leaving group; 2) intramolecular SN2 displacement; and 3) oxidative addition across the N-O linkage. This affords transient {P^P}CuIII intermediate 5, from which P and 6 are likely formed upon C-N bond-forming reductive elimination. The generation of the branched tertiary amine product Pa in a single step through nucleophilic attack of the Cu-C linkage at the positive N(amine) centre with concomitant N-O bond cleavage has been probed as a further plausible mechanistic avenue ( dashed arrow in Scheme 2). Given that hydrocupration proceeds with strict 2,1 regioselectivity, the discussion will focus exclusively on pathways that commence from 4a. Notably, rival paths starting from 4b are found energetically non-competitive in every case studied. The full account of all the studied pathways can be found in the Supporting Information. We start with examining N-O bond cleavage of 1b by nucleophilic {P^P}CuI benzyl 4a. Figure 5 collates the free-energy profile of the most accessible pathway for the various mechanistic scenarios examined, whilst structural aspects of key species involved can be found in Figures S4-S9 (see the Supporting Information). The electrophile 1b binds preferably via its N donor centre (à ¯Ã‚ Ã‚ «1-N) at copper to furnish adducts with the unbound carboxylate oxygen pointing either towards (4a1†¢A) or away (4a2†¢A) from the metal, both of which are higher in free energy than the separated fragments. The located TS[4a2†¢A5a] structure describes N-O bond cleavage that is reminiscent of a SN2 displacement of the benzoate group, featuring distances of 1.72 and 2.02 Ã… for vanishing N-O and emerging Cu-N amido bonds (see Figure S5 in the Supporting Information). Progressing further along the reaction trajectory, the benzoate group binds eventually at copper to deliver transient { P^P}CuIII intermediate 5a. The intramolecular process version commencing from 4a1†¢A evolves through a five-centre TS[4a1†¢A-5a] that displays similar metrics regarding vanishing N-O and emerging Cu-N amido bonds, but crucially benefits from an already pre-established Cu-O(benzoate) contact (see Figure S7 in the Supporting Information). As it turns out, this contact likely renders 4a1†¢A→5a intramolecular SN2 displacement somewhat favourable kinetically over 4a2†¢A→5a with both pathways are indistinguishable on thermodynamic grounds. The TSOA[4a2†¢A-5a] shown in Figure 5 (see also Figure S9 in the Supporting Information) has been located as energetically prevalent three-centre TS structure describing oxidative addition across the N-O linkage that occurs at distances of 2.43 Ã… and 1.89/2.60 Ã… for vanishing N-O and newly built Cu-N(amido)/Cu-O bonds, respectively. The condensed free-energy profiles in Figure 5 reveal that for cleavage of the electrophiles N-O linkage by {P^P}CuI benzyl nucleophile the 4a1†¢A→5a intramolecular SN2 pathway (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 19.8 kcal mol-1 relative to {4a+1b}) prevails kinetically somewhat over 4a2†¢A→5a, with oxidative addition proceeding through TSOA[4a2†¢A-5a] (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 31.1 kcal mol-1 relative to {4a+1b}) is found substantially more demanding kinetically and hence not accessible. The fine energy balance between the alternative SN2-type pathways is likely be influenced by the diphosphine catalyst backbone. Figure 6 combines the dominant pathway for N-O bond cleavage at amine adduct 4a†¢A with C-N bond-generating reductive elimination at transient {P^P}CuIII 5a taking place thereafter. Given that benzyl and amido functionalities are already preferably arranged in 5a no major structural reorganisation is required prior to traversing TS[5a6†¢Pa], which occurs at a distance of 2.36 Ã… of the emerging C-N bond (see Figure S11 in the Supporting Information) and decays thereafter into the branched tertiary amine product that is initially bound to {P^P}CuI benzoate (6†¢Pa), but is readily released thereafter. The reductive elimination is found highly facile (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 5.2 kcal mol-1 relative to 5a) and driven by a remarkably strong thermodynamic force (Figure 6). Of the two consecutive steps converting {P^P}CuI benzyl 4a into amine product Pa and {P^P}CuI benzoate 6 through interception with electrophile 1b, the first intramolecular SN2 displacement of the ben zoate leaving group determines the overall kinetic demands (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 19.8 kcal mol-1 relative to {4a+1b}) with Pa and 6 are then generated from transient, highly reactive {P^P}CuIII intermediate 5 upon rapid and strongly downhill reductive elimination. Nucleophilic attack of the Cu-C linkage at the positive N centre of the amine electrophile with concomitant N-O cleavage, thereby affording 6a + Pa in a single step, describes an alternative mechanistic scenario. Despite all our efforts, a precise TS structure associated to this pathway could not be located, but examination by means of a state-of-the-art reaction-path-optimisation (chain-of-state; see the Computational Methodology) method provided a reasonably approximate TS structure. The multicentre TS[4a1†¢A-6†¢Pa] describes concerted N-O bond cleavage (2.30 Ã…) together with C-N (2.54 Ã…)/Cu-O(2.37 Ã…) bond formation, all occurring in the immediate vicinity of the copper centre (see Figure S12 in the Supporting Information). A substantial barrier of approximately 30.7 kcal mol-1 (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ relative to {4a+1b}) has to be overcome (Figure 7), which renders the concerted 4a1†¢A→6†¢Pa pathway non-accessible kinetically in the presence of the viable two-step conversion shown in Figure 6.[16] {P^P}CuI benzoate compound In light of the strong thermodynamic force associated with generating the C-N bond, the {P^P}CuI benzoate may become, among others, a candidate for the catalyst resting state. Hence, the aptitude of 6 to accommodate additional reactant, amine product and THF solvent molecules has been probed in order to clarify its precise identity. In accordance with findings for 2 and 3, a single molecule only can bind at copper at the expense of one of the two Cu-O(carboxylate) linkages, but adduct formation is disfavoured in terms of free energy. Hence the {P^P}CuI benzoate is predominantly present as non-adducted form 6 featuring a à ¯Ã‚ Ã‚ «2-O ligated benzoate functionality (Figure 8). Regeneration of {P^P}CuI hydride from {P^P}CuI benzoate Transmetalation of 6 with trimethylsilane 1c regenerates the catalytically competent {P^P}CuI hydride 3 for another catalyst turnover, thereby closing the cycle for productive HA catalysis. Two scenarios have been analysed that are distinguished by which of the carboxylate oxygens at silane adducted 6†¢H participate in Si-O bond formation. The transfer of silyl onto the oxygen directly bound to Cu evolves through a four-centre metathesis-type TS[6†¢H-3†¢OS1] and leads eventually to 3 upon facile liberation of Me3SiOBz. On the other hand, a six-centre TS[6†¢H-3†¢OS2] is traversed along an alternative pathway representing silyl transfer onto the unbound carboxylate oxygen (Figure 9 and Figure S13 in the Supporting Information). The enhanced stability of six-centre TS[6†¢H-3†¢OS2] versus four-centre TS[6†¢H-3†¢OS1] discriminates among the two pathways, which are driven by a thermodynamic force (à ¯Ã‚ Ã¢â‚¬Å¾G = 0.5 kcal mol-1 relative to {6 + 1c}) of identical magnitude. The assessed barrier of 26.2 kcal mol-1 (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ relative to {6 + 1c}) for the most accessible pathway characterises 6 + 1c→3 + Me3SiOBz as a kinetically demanding, but viable transformation that is slightly uphill thermodynamically (Figure 9). Reduction of the benzylamine ester by {P^P}CuI hydride The well known tendency of the catalytically competent {P^P}CuI hydride to reduce the amine electrophile under N-H bond formation, hence giving rise to {P^P}CuI benzoate, or alternatively via O-H bond formation to afford a {P^P}CuI amido can severely compromise the catalyst performance. To this end, several conceivable pathways (some of which are sketched in Scheme 2) have been studied. Whilst focusing on thermodynamic aspects amine reduction with N-H bond formation via 3 + 1b→6 + HNMe2 (à ¯Ã‚ Ã¢â‚¬Å¾G = -71.9 kcal mol-1) appears to be strongly favoured over O-H bond generating 3 + 1b→{P^P}CuI(NMe2) + benzoic acid (à ¯Ã‚ Ã¢â‚¬Å¾G = -51.3 kcal mol-1). The cleavage of the N-O linkage of 1b at amine adduct 3†¢A does preferably proceed through SN2 displacement of the benzoate leaving group with the intramolecular pathway proved to be somewhat favourable energetically (see Figure S14 in the Supporting Information), whilst oxidative addition of electrophile 1b across the N-O linkage is found substantially more demanding kinetically. All these aspects closely parallel the findings regarding the preferable avenue that leads to generate {P^P}CuIII 5a (see above). Likewise, N-H bond-forming reductive elimination at {P^P}CuIII amido hydride intermediate 7 is highly facile kinetically and strongly downhill as 5a→6a + Pa is. Unfortunately, all the efforts to localise the associated TS structure have not been successful, but the examination of the reaction path thoroughly by means of a chain-of-state method firmly indicates that reductive amine elimination at 7 has an only marginal barrier, if at all, to overcome, hence it proceeds almost instantaneously. Overall, a smooth, kinetically affordable pathway for undesired 3 + 1b→6 + HNMe2 conversion has been located that comprises a first intramolecular SN2 cleavage of the N-O bond (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 26.3 kcal mol-1 relative to 3dim, Figure 10), to be followed by highly rapid reductiv e amine elimination from an intervening and highly reactive {P^P}CuIII intermediate 7, thus reflecting the well-documented aptitude of 3 to engage in performance-limiting reduction of the electrophilic amination reagent.[6, 7] Further attempts devoted upon locating a proper TS structure for the concerted attack of the nucleophilic Cu-H linkage at the N centre of the amine electrophile to be accompanied with N-O bond disruption has not been successful. However, a reasonably approximate TS (see Figure S15 in the Supporting Information) is seen to be above TS[31†¢A-7] by another 19.8 kcal mol-1, such that the concerted pathway can confidently be discarded as energetically viable alternative to the operative two-step process. Proposed catalytic cycle The mechanistic picture based upon the above thoroughly conducted examination of relevant elementary steps is presented in Scheme 3. An energetically smooth and downhill sequence of steps transforms the starting material into the catalytically competent {P^P}CuI hydride 3, which is in a mobile equilibrium[11b] with its thermodynamically prevalent dimer 3dim. Migratory insertion of the styrene C=C linkage into the Cu-H bond is kinetically facile (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 21.6 kcal mol-1 relative to { ½3dim+1a}), thermodynamically downhill and proceeds with strict 2,1 regioselectivity. Hence irreversible hydrocupration is regioselectivity determining and occurs prior to the turnover-limiting step. The interception of the thus generated secondary {P^P}CuI benzyl 4a with amine electrophile 1b produces the branched tertiary (Markovnikov) amine product Pa and {P^P}CuI benzoate 6. This transformation favours a two-step process comprising the first intramolecular SN2 displacement of the b enzoate leaving group (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 19.8 kcal mol-1 relative to { ½3dim+1a+1b}) to furnish transient, highly reactive {P^P}CuIII intermediate 5 from which Pa and 6 are generated upon highly rapid and strongly downhill reductive elimination. It renders 6 to be the most stable species of the cycle for productive HA catalysis and it thus corresponds to the catalyst resting state. The regeneration of catalytically competent 3 from 6 through transmetalation with hydrosilane 1c is found most demanding, but affordable, kinetically (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 26.2 kcal mol-1 relative to {6+1c}) and hence is turnover limiting its assessed barrier is compatible with reported catalyst performance data.[6] It is worth mentioning that a similar picture regarding hydrocupration and transmetalation steps has emerged from a recent experimental study by the Buchwald group on a DTBM-SEGPHOS-based CuI catalyst.[7d] A stepwise pathway closely related to 4a†¢A→6 + Pa is preferably traversed for the non-productive reduction of amine electrophile by 3. An intramolecular SN2 N-O bond disruption (à ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 26.3 kcal mol-1 relative to { ½3dim+1b}) precedes highly facile and strongly downhill reductive amine elimination from intervening, highly reactive {P^P}CuIII intermediate 5a. The assessed small kinetic gap (à ¯Ã‚ Ã¢â‚¬Å¾Ãƒ ¯Ã‚ Ã¢â‚¬Å¾G†¡ = 0.1 kcal mol-1) between discriminative TS structures for productive and non-productive reaction branches reflects adequately the observed close competition between the two processes, which can lead to compromised catalyst performance for improper chosen amine electrophiles. Furthermore, it provides further confidence into the substantial predictive ability of the herein employed high-level computational methodology.[17] Effect of the amine electrophile upon catalyst performance A second part of this study explores the effect of the amine electrophile upon catalyst performance. To this end, the energy profile for two

Multi Agency and Intergrated Working

Multi-agency working and integrated working are extremely important as it benefits the child, their family and the practitioners in a huge way. Definitions of these ways of working are below. Multi-agency Working – This is where practitioners from different services and professions come together to provide integrated support for children and families with additional needs. Integrated Working – this is where different services, agencies, professional and practitioners work together to put the child at the centre to help improve their lives and met their needs and offer effective care for the child. Integrated working and multi-agency working delivers better outcomes for the children and families as there is a broad range of knowledge, skills and professions all trying to do their best for the child. More ideas and opinions and record sharing will allow us to achieve the best possible outcomes for the child. To make sure the outcomes for the child are to be positive we must make sure that all parties understand what information can be shared and about the importance of confidentiality. External agencies There are many external agencies that we may meet that are brought in to support a child and their family. Some may work in their own setting and some are integrated into children centre and schools. Below is a list of some of these agencies and a brief description of their roles. Speech and Language Therapists – are employed by the local primary care trust and support individual children and their families. A referral can be made by a gp/health visitor and an awareness raised by a setting. They will work closely with the family and the setting. Educational psychologists – are employed by the local authority and will give support to children with specific learning or psychological needs. They require a referral from the setting. Physiotherapist – are employed by the local primary care trust and will support children with a specific physical need. A referral is required either from a health professional or a setting. Play specialist – May work with social services supporting children in difficult a family situation or can support children in a hospital setting. Behavioural support service – are part of the local authority and works in partnership with schools to help promote positive behaviour. They work within a framework of inclusion and also provide effective support to pupil, parents and schools where behaviour is a concern and may effect the child’s achievement. Social workers – employed by social services and may also be attached to a children’s centre, they will support children and their families to help family issues involving health need, poverty, bereavement etc. and also help to improve their housing. Common barriers to multi-agency working and integrated working There are many common barriers to multi-agency working and integrated working, these barriers will affect the outcome to the child. Some of the common barriers are explained below. Professional status and professional pride – this is where people who are highly trained/qualified, find it hard to cope with being managed/lead by a person with different/lower qualifications. Different professional priorities – all professionals deal with risks, situations and priorities in different ways and orders they may not agree with others. Language and terminology – all professionals use words, phrases and abbreviations that relate to their area of expertise and other professionals who work in different areas/specialities will not understand these. Poor communication skills – information may not be shared by all, poor methods of communication and people not receiving information/communication is a big issue. For example if information is shared by email and two workers don’t have email they will not receive the information. It is important to remove these barriers from the start before they become an issue and affect the outcome. The key to this is to put in place a lead professional. This person would co-ordinate communication, they will act as the point of contact for the child and family. The lead professional will need to set rules and discuss things such as people preferred method of communication as we are not all the same and the lead professional must make sure they use each persons preferred method. The lead professional must also ensure that all people have a copy of the rules and ensure that if any jargon/terminology is used it is first explained to the group, all these things will help prevent barriers and ensure a good outcome for the child and their family. Referrals between agencies Within the setting it may become necessary to refer a child to another professional for additional support, for example if it has been noticed that a child of 3 is having issues which speech that he cannot say many words and the ones that are said are not clear, then the child would benefit from support from speech and language therapist then a referral is needed the setting would follow the steps below to make the referral.First of speak with the parent/carer/child about the issue and gain consent to make the referral.Next you would need to identify the service/agency who you want to refer to.Then you would need to contact the agency and discuss the situation before making the referral. We do this to make sure the agency can offer the most suitable service/support that is needed.Next follow the agency’s referral procedure completing all necessary paperwork and return by referral deadline if required. Always keep a copy of the referral.Follow up the referral and find out the d ecision. Common Assessment FrameworkIn the Children Act 2004 and Every Child Matters it is outlined that the Common Assessment Framework (CAF) is a way ensuring early intervention for a child before they reach a crisis point. CAF is a shared assessment and planning framework in all areas of England and Northern Ireland to be used by all practitioners working in children’s services. The main aim of CAF is to make sure that a child’s additional need is identified early and to ensure that agencies work together to meet the additional needs of the child. The CAF consist of four main partsA pre-assessment checklist to help decide who would benefit from a common assessment.A process to enable practitioners in the children and young people’s workforce to undertake a common assessment and then act on the result.A standard form to record the assessment.A delivery plan and review form. The assessment covers three domains: development of the child or young person; parents and carers; and family and environment.The CAF can be used on children from 0 to 19 years and also 19 to 24 years where necessary, and any professional, parent or even child can request that a CAF is undertaken. As with a normal referral you need consent to do a CAF either from the parent, carer or the child. There are four main stages in completing a common assessment  Identifying needs early.Assessing those needs.Delivering integrated services.Reviewing progress I have completed a mock CAF form (enclosed) to show how the form is to be completed.

Doctor Zhivago For The Most Part Was Set During The Time...

Summary, context of the era depicted, description of major social, economic, or cultural forces in the era and how the film addressed nature of the era: Doctor Zhivago for the most part was set during the time of World War I , spans the Russian revolution and civil war. It also moves through the â€Å"terror of the thirties†, where the main character Doctor Zhivago was able to survive through all of it, and ends in the mid-1940s (Howe, 2013). The movie starts and ends in the late 1940s to early1950s and opens with KGB Lieutenant General Yevgraf Zhivago trying to search for the girl that was the child of Doctor Yuri Zhivago and Lara. Yevgraf brings in a young girl, Tonya Komarova, who he thinks may be his niece and he begins to tell her the†¦show more content†¦The movie moves to Lara who is told to go to a dinner in her mother’s place because she had a fever just before they were to leave. She went with Victor Komarovsky, a friend of her mother s. Lara is apparently Victor’s niece but that was not made to be an important factoid. Victor is a powerful and rich figure in Russian society just based on his c omments like â€Å"do you have any idea how expensive this meal is?† Earlier in the movie, a reformer named Pasha Antipov is passing out fliers to a crowd. The fliers are for a peaceful rally that is pushing for a revolution. That night after Lara comes home from dinner with Victor Komarovsky, Pasha Antipov, who we find out later is going to marry Lara, comes to Lara’s house after being injured by the Cossacks who came out to forcefully stop a peaceful protest. Pasha goes to Lara because he needs help treating the cut on his face. There is a bit of foreshadowing when they grab the bottle because later on Lara s mother finds her messing out with Victor Komarovsky and tries to use what was in the bottle to commit suicide. Victor Komarovsky sends a letter to get assistance from the doctor but he sends it to a doctor who was really far away. When the letter arrives, Zhivago just happens

I Have A Dream and the Civil Rights of African Americans

Through the years of history we find ourselves wondering how the colored people first got their freedom from the whites and how they stopped the racial segregation. There was one important man in history, which helped us see the hope to win the freedom for the colored people. Martin Luther King was a Civil Rights Activists, he who had a dream one day to free the colored people from the whites and to change the outlook on how people see the colored, he also had a dream of every man is born and created equally despite the different skin colors. The man who once said: â€Å"I Have a Dream Today†(3) has proven his dream to help the rest of us live out our lives with equal rights and the same amount of freedom equally for everyone despite the color of skin that we were born with. He was the only person along with Rosa Parks to stop the racial segregation not just in one country but around the world, they have both given history the meaning along with many others who have helped cha nged the world for the better. I Have a Dream speech on this day sometime in March in Washington is known as the single most important Civil Rights rally in history. It served as a sign to the Civil Rights act of 1964 and the Voting Rights act of 1965. Martin Luther King was shot and killed when he was 39 by a man named James Earl Ray on April 4, 1968. About two hundred thousand people marched at his funeral march. Dr. King’s speech did not comprehend any politics or detailed plans or programs of any sort,Show MoreRelatedMartin Luther King Jr.1332 Words   |  6 PagesMartin Luther King Jr. was a leader in the Civil Rights Era, advocating for the Civil Rights Act’s passage and eventually passage of the Voting Rights Act in the 1960s. In his capacity as a Civil Rights leader, MLK delivered his famous â€Å"I have a dream† speech after the march for Civil Rights in Washington, D.C. His speech was delivered on August 28th in front of the Lincoln Memorial. In his s peech, MLK made sure to emphasize the hope that many African Americans had in the United States. Furthermore,Read MoreMartin Luther King Speech Analysis989 Words   |  4 Pagesof time. His words sparked change for an entire nation and was an enormous factor in contributing to the African American Civil Rights movement. During the time of Martin Luther King Jr’s speech, the country was in a great state of distress regarding equal rights and equal opportunity for people of color. Riots, protests, and chaos seemed to be taking over the country as African Americans began to demand their deserved equality. Martin Luther King Jr stepped up through all the madness going onRead MoreI Have A Dream By Martin Luther King Jr.983 Words   |  4 Pageswho fought for the rights of African-American. During the late 1950s and early 1960s, America was on the brinks of collapsing towards a civil right war. Leaders were across the United States creating factions of people. However, King J r. was not an ordinary leader. He was a man with a dream. A dream that he constantly, throughout his speech, is talking about. A dream where there is no discrimination among people and freedom is equal for everyone. In his speech, â€Å"I Have a Dream†, Martin Luther KingRead MoreRhetorical Analysis Of I Have A Dream Speech923 Words   |  4 Pagesyears to come. Dr. King wrote his â€Å"I Have a Dream† speech for the March on Washington for which he presented his speech in front of thousands of Civil Rights protesters and activists. In this exhortation, Dr. King beats down the issues of human rights, Jim Crow laws, and racism with the rhetorical strategies of metaphors, anaphoras, and ethos. In King’s â€Å"I Have a Dream† speech, metaphors are used to illuminate the struggles of African-Americans gaining equal rights and the oppression they feel throughRead MoreCivil Rights/Secret Life of Bees986 Words   |  4 Pagesvery first African Americans arrived in America, coming over for the purpose of forced slavery. It’s been nearly four hundred years since then and African Americans are still not treated completely equal. But throughout the years major steps towards equality have been made and as a whole the United States is close to reaching this goal. The first key action taken was abolishing slavery in 1865, but African Americans didn’t start gaining equal rights until 1955 during the Civil Rights Movement. TheRead MoreThe Era Of Freedom : A Generation After The Emancipation Proclamation1599 Words   |  7 PagesThe Era of Freedom A Generation after the Emancipation Proclamation, banned slavery, African Americans were trapped in a country full of harsh discrimination, and humiliation. The twentieth century brought an era that changed the lives of every African Americans across the U.S. The Civil Rights Movement, a movement to sees the cruelty that every African American faced on a daily bases, was one of the greatest events that took a step into a direction that no one would ve imagined during theRead MoreMartin Luther King, Speech Research1572 Words   |  7 PagesIntroduction- English, speech I have a dream was one of the most powerful and influential speeches of all time, it not only created the realisation that the Negro was not free, it persuaded that of white people to make a change for the benefit of the African Americans. The African American civil rights movement was creeping forward but two individuals created a greater atmosphere for the reinforcement of the movement, sure William Wilberforce abolished the slave trade for Britain in 1807, and thatRead MoreMartin Luther King Jr. Dr. Martin Luther King Jr. is unarguably the most famous civil rights900 Words   |  4 Pagesunarguably the most famous civil rights activist in American history. His story and legacy is taught in classrooms across the country. From birth to death, Dr. King impacted the lives of many people and changed the roles of society forever. Dr. King had one big dream and what shaped his dream begins in Atlanta,, Georgia, and ends in Memphis, Tennessee. Dr. Martin Luther King Jr. was born into a loving and caring family on January 15, 1929 in Atlanta, Georgia. As an African American, he attended many segregatedRead MoreThe Rhetorical Analysis Of Martin Luther Kings Speech895 Words   |  4 PagesMartin Luther King was a Baptist minister and social activist who spent countless years, fighting for a civil rights. It was on the date of August 28th, 1963, on the steps of the Lincoln memorial is where King made his leap of faith and spoke out on the injustice of African Americans. His dream for African Americans to be equal, appealed to the emotions of his audience. The desire to live a civil life and not be oppressed was felt by many. Martin Luther King delivered a speech that would immenselyRead MoreMartin Luther King And King Remembered By Malcolm X Analysis804 Words   |  4 Pagespublic high schools unconstitutional. A few years later, the Civil Rights Act and Voting Rights Act for African Americans were passed. During, these ye ars civil and economic rights were being diligently fought for. The unity of all African Americans regardless of their religion, political views, or social was being encouraged. Speeches and rallies also took place to end racism and instill equality. There is no doubt any of this would have been accomplished without the help of notable activists Martin