This is the accepted version of the journal article: Gómez-Orellana Seguín, Pablo; Lledós, Agustí; Ujaque Pérez, Gregori. «Com- putational analysis on the Pd-catalyzed C-N coupling of ammonia with aryl bromides using a chelate phosphine ligand». Journal of organic chemistry, Vol. 86, Issue 5 (March 2021), p. 4007-4017. DOI 10.1021/acs.joc.0c02865 This version is available at https://ddd.uab.cat/record/274347 under the terms of the license Computational Analysis on the Pd-Catalyzed C-N Coupling of Ammonia with Aryl Bromides Using a Chelate Phosphine Ligand Pablo Gómez-Orellana, Agustí Lledós* and Gregori Ujaque* Departament de Química and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Catalonia, Spain email: agusti@klingon.uab.es; email: gregori.ujaque@uab.cat KEYWORDS DFT calculations, C-N Coupling, Pd catalyst, Reaction Mechanism, Ammonia ABSTRACT The Buchwald-Hartwig amination of arylhalides with the Pd-Josiphos complex is a very useful process for the generation of primary amines using ammonia as reactant. DFT calculations are carried out to examine the reaction mech- anism for this process. Despite the general mechanism for the C-N cross-coupling reaction is known, there are still some open questions regarding the effect of a chelate phosphine ligand and the role of the base on the process. Reaction pathways involving the release of one of the arms of the phosphine ligand are compared with those where the chelate phosphine remains fully coordinated. Conformational analysis for the complex with the open chelate phosphine is required to properly evaluate the proposed pathways. The role played by the added base (t-BuO⁻) as a possible ligand or just as a base was also evaluated. The understanding of all these aspects allowed us to propose a complete reaction mechanism for the Pd-cata- lyzed C-N coupling of arylhalides with ammonia using the chelate Josiphos ligand. INTRODUCTION ligands of the metal complex generating stable intermedi- ates that prevent the further development of the reaction.13 The Buchwald-Hartwig amination1,2,3,4,5 is a chemical reac- The application of homogenous transition metal catalyst tion used in organic chemistry for the synthesis of carbon- for the selective synthesis of amines from ammonia under nitrogen bond containing products. The reaction is a cou- mild conditions is appealing, however, the development of pling of amines with aryl halides via a palladium-catalyst.6,7 such transformations is challenging; it would allow the This process has simplified the synthesis of pharmaceutical functionalization of aryl and aliphatic chains to form pri- and agrochemical agents, among others relevant chemi- mary amines.14,15,16 cals. It has advantages over other methods as good func- tional group compatibility and necessity of relatively mild conditions. 8,9,10 Primary and secondary amines are the common reactants in this type of coupling C-N reactions.11 Nevertheless, the use of the ammonia, an inexpensive bulk chemical, is ra- ther uncommon despite its potential for producing pri- mary amines.12 The major disadvantages of ammonia as re- actant in homogenous catalysis are mainly related to its high basicity and strong N-H bond. The ammonia is a strong Lewis base that can cause the displacement of the 1 Figure 1: (a) C-N cross-coupling reaction using NH3 devel- amination process for the NH3 amine when a chelate oped by Hartwig`s group. (b) Scheme of Josiphos (CyPF- biphosphine ligand as Josiphos is employed, we performed tBu) ligand. a computational analysis of the reaction mechanism. In 2006 Hartwig’s group reported that a Pd complex along with the Josiphos chelate ligand was able to catalyse the RESULTS AND DISCUSSION coupling between ammonia and arylhalides (Figure 1). 13,17, ,18 A related Pd-catalysed process for the coupling between The general reaction mechanism for the Buchwald Hartwig aryls and ammonia was also developed by Buchwald using amination can be divided in four main steps as shown in biaryl phosphines.19,20 These are among the few cases Figure 2.37,39 The oxidative addition and reductive elimina- where ammonia was employed as reactant. 21,22,23,24,25, ,26,27,28 tion steps should not be significantly affected by a chelate phosphine. The amine binding, however, could be signifi- Understanding and rationalizing the synthetic tools that cantly modified. Moreover, in addition to the amine, the employ small reactants (i.e. NH3 or H2O) as starting ma- base may also coordinate the catalyst; thus, deprotonation terial to produce higher added value chemicals is highly can be also modified. Therefore, for analytical purposes the desirable.29,30,31,32,33 Computational chemistry is an excellent possibility for ligand substitution and proton transfer are tool to investigate catalytic reactions.34,35 The reaction considered together. mechanism of the Buchwald-Hartwig amination consider- ing the active Pd-catalyst with conventional phosphine lig- The first and third sections describe the results for the ox- ands was initially described from a theorical point of view idative addition and reductive elimination steps. The sec- by Cundari,36 Harvey and Fey,37 Organ38 and Norrby39 ond one is divided in four subsections each one devoted to groups. More recently, the effect of biaryl phosphines, each of the alternatives for the ligand substitution process ylide-substituted phosphines and meta-terarylphosphine / deprotonation that has been considered. Finally, the last ligands were computationally evaluated by Baik,33,40 Ma,41 section collects all the results and describes the overall Gessner42, Jong and Lim43 groups, respectively. The mech- mechanistic proposal. anism for Pd-NHC catalysed C-N coupling was also re- cently analysed.44 The general mechanism is generally di- Oxidative Addition vided in four main steps (Figure 2): 45,46,47,48,49,50,51 (i) oxida- The catalytic cycle starts with the interaction of the aryl tive addition of the aryl halide, (ii) amine coordination, (iii) bromine with Pd-Josiphos complex, I. The Pd-Josiphos is amine deprotonation and halide release, and (iv) reductive an asymmetric phosphine, thus, the oxidative addition of elimination. PhBr may take place through two different pathways de- pending on the relative position of halide and phenyl within the square planar intermediate. The formation of a complex with the phenyl trans to P2, intermediate II, lo- cated at -18.3 kcal mol-1, must overcome an energy barrier of 8.7 kcal mol-1, TS_I (Figure 3). The product of the oxida- tive addition for the pathway giving rise to the phenyl group trans to P1, intermediate II_op, has a Gibbs energy of -14.5 kcal mol-1; the transition state, TS_I_op, has an en- ergy of 13.4 kcal mol-1 (Figure 3). Figure 2: General catalytic cycle for Buchwald-Hartwig amination with monodentated phosphines (L). The reaction mechanism for a bidentate ligand as Josiphos, however, has not been analysed in detail yet. Norrby made some useful suggestions is his mechanistic analysis, that was mostly focussed on the role of the base in the reaction, but without calculating the reaction profiles for the chelat- ing system.39 There are many particularities that are not known, as whether the chelate phosphine remains bicoor- dinated or not during the complete reaction, or if the t- Figure 3: Gibbs energy profiles for the oxidative addition in BuO⁻ plays an exclusive role as a base or it also acts as a 1-4 dioxane (kcal mol-1). ligand during the substitution process. Thus, with the aim The oxidative addition through an aromatic nucleophilic of providing an overall picture for the Buchwald-Hartwig substitution path (SNAr) was also evaluated.52,53,54,55 The 2 transition state TS_I_Snar is located at 21.6 kcal mol-1 com- pared to intermediate I. The Gibbs energy barrier is 12.9 - Pathway A kcal mol-1 higher than that for TS_I, therefore, it can be dis- In this pathway the t-BuO- plays a double role as a nucleo- carded for this process in agreement with other works. 52,56,57 phile substituting the bromide in the coordination sphere of palladium, and as a base deprotonating the coordinated The most accessible pathway for the addition gives rise to ammonia. intermediate II, with the phenyl group trans to P2 and the The Gibbs energy reaction profile is shown in Figure 4. In- bromide trans to P1. Both, the relative energy barrier (by termediate II_A, with a relative energy of -14.2 kcal mol-1 4.7 kcal mol-1) and stability (by 3.8 kcal mol-1) support the due to the presence of the (t-BuONa)4 cluster, undertakes formation of intermediate II over intermediate II_op. This two consecutive ligand replacements on the complex. In step is irreversible (vide infra), thus, the subsequent steps the first one, a t-BuO⁻ substitutes the Br⁻ in the coordina- of the reaction mechanism are analysed from this interme- tion sphere of the metallic center; the transition state diate. TS_II_A1 is located at 10.2 kcal mol-1, with a relative Gibbs energy barrier of 28.5 kcal mol-1. This step involves not only Ligand Substitution and proton transfer a ligand replacement but also the dissociation of one of the For the steps involving ligand substitution and proton t-BuO- anions from the cluster. The transition state shows transfer processes we envisioned four different pathways as a trigonal bipyramidal geometry around the Pd center, represented in Scheme 1. The difference between the two with Ph and P2 occupying the apical positions, respectively first pathways, both keeping the phosphine chelate coordi- (Figure 5). The intermediate formed, III_A1, where t-BuO⁻ nated along the reaction, is related to the role played by has replaced Br⁻ has a Gibbs energy of-10.0 kcal·mol-1, (Fig- the base in the mechanism. In pathway A the t-BuO- sub- ure 5). Then there is the substitution of the base (t-BuO-) stitutes the halide in the coordination sphere of the metal, by the amine (NH3) along with the proton transfer from and then it is replaced by the ammonia; the t-BuO- plays a NH3 to the t-BuO⁻. The relative Gibbs energy barrier for double role, as a ligand and as a base. In pathway B, the this step, TS_II_A2, is 13.5 kcal mol-1. It involves a ligand halide is substituted directly by NH3, and the t-BuONa acts replacement along with amine deprotonation giving rise to exclusively as a base subtracting the proton. Pathways C intermediate IV_base_A, located at -15.2 kcal mol-1. This and D are analogous but taking into consideration that the intermediate is ready for the reductive elimination process phosphine can dissociate one of the arms thus offering an (see below). open coordination site. Figure 4: Gibbs Energy profile for pathway A. Gibbs ener- gies in kcal mol-1. Scheme 1: Reaction pathways evaluated for the Buchwald- Hartwig amination with ammonia catalysed by Pd-Josi- phos. 3 Figure 5: Optimized geometries for: (a) III_A1, (b) TS_II_A1, and (c) TS_II_A2. Distances in Å. - Pathway B This pathway considers that t-BuO-only plays a role as a base in the reaction. The Gibbs energy profile is shown in Figure 7: Optimized geometries for: (a) III_B2, (b) TS_II_B Figure 6. The replacement of the bromine by ammonia and (c) TS_III_PT. Distances in Å. takes place through TS_II_B; it presents a trigonal bi- For both pathways A and B, five coordinated intermediates pyramidal geometry with the incoming NH3 and leaving for the ligand substitution were searched. Nevertheless, as Br- at equatorial positions (Figure 7). The relative Gibbs en- expected for a Pd(II) complex, they could not be located on ergy barrier is 20.8 kcal mol-1. The intermediate formed, the potential energy surface. Only transition states for the III_B1, has a relative Gibbs energy of -16.6 kcal mol-1. The ligand substitution showed trigonal bipyramidal geome- calculation of the proton transfer from coordinated NH3 to tries (Figures 5 and 7). the base considers the latter in its cluster form. Thus, in- Pathways A and B consider the chelating phosphine fully termediate III_B2, including the cluster is at -6.1 kcal mol- 1. The energy barrier for the proton transfer, TS_III_PT, coordinated along the path. Pathway B is preferred over A since the ligand substitution of Br⁻ by NH3 is favoured over was estimated to be 12.7 kcal mol-1 from III_B1.58 The inter- its substitution by t-BuO-. In pathway A, the proton trans- mediate formed, IV_Base, with a relative Gibbs energy of - fer is a barrierless process once NH3 is coordinated to the 10.0 kcal mol-1, is analogous to that of the previous pathway Pd center, because the t-BuO- has been previously dissoci- and ready for the reductive elimination. ated through transition state TS_II_A1. In pathway B, how- ever, it is necessary to overcome a low energy barrier of 2.2 kcal mol-1 (from III_B2 to TS_III_PT; Figure 6) due to the dissociation of the t-BuO- from the cluster. - Pathway C The next two pathways describe parallel mechanisms to those previously described but considering that one of the arms of the chelate phosphine can dissociate. The dissoci- ation of the phosphine generates an additional issue re- garding the conformational flexibility since there are many conformational possibilities for the monodentate Josiphos Figure 6: Gibbs energy profile for Pathway B in 1-4 dioxane phosphine. To overcome this issue, we performed a con- (kcal mol-1). * Value estimated in the absence of Br⁻ from formational analysis for such an intermediate. the calculation. In pathway C the first step is the replacement of a phos- phine arm by the ammonia ligand. For an asymmetric phosphine such a replacement can generate two different 4 intermediates depending on the substituted phosphine this intermediate, NH3 and Br⁻ ligands must interchange (Scheme 2). their coordination sites to produce an intermediate with the aryl and ammonia ligands in cis position, III_C2. Com- putational evaluation of the isomerization of these ligands on a Pd(II) square-planar complex is not an obvious task. Nevertheless, it has been experimentally shown that it is a Scheme 2: Dissociation of the phosphine arms by the nu- rather easy process;61,62 thus, we can assume that the isom- cleophilic attack of the ammonia: P2 (III_C1) and P1 erization is feasible within this pathway. (III_C1’). For the conformational analysis we first developed the force field parameters for the metal center (see computa- tional details). Then MD calculations were run at high tem- perature (1000 K) to explore the conformational space. Fi- nally, the structures saved during MD were clustered to ob- tain the most representative conformations for each inter- mediate. These structures were subsequently optimized at QM level to check their relative Gibbs energies (see Sup- porting Information). A similar conformational study was performed for each of the two possible intermediates, III_C1 and III_C1’ (Scheme 2). The results are gathered in Table 1. The values obtained point out the importance of Figure 8: Gibbs energy profile involving phosphine dissoci- conformational effects when computing catalytic cycles ation of P2 (Pathway C) in 1-4 dioxane (kcal mol-1). * Value with flexible ligands.35,59 ,60 estimated in the absence of Br⁻ from the calculation. Conformations related to III_C1’ intermediate are in the range of 8 to 30 kcal mol-1, always much higher in energy. Thus, they will not be further considered. For III_C1 inter- mediate, the most stable one (conf. 4) was selected to study this reaction pathway. There are other conformations that may be also suitable for this mechanism, but for analytic purposes we selected this one (it does not modify the con- clusion of the work because this is the most favoured path- way). Table 1: Gibbs relative energies (kcal mol-1) for conformers of intermediates III_C1, III_C1’ and III_C2. Conformations ΔΔGsolv ΔΔGsolv ΔΔGsolv III_C1 III_C1’ III_C2 Conf. 1 4.8 10.7 2.7 Conf. 2 6.2 16.4 -2.2 Conf. 3 3.7 11.3 0.5 Conf. 4 0.0a 10.6 2.3 Conf. 5 0.7 8.1 4.5 Conf. 6 2.8 21.1 16.8 Figure 9: Optimized geometries for: (a) TS_II_C1, (b) TS_II_C2. Distances in Å. Conf. 7 5.1 21.7 11.2 In order to evaluate the relative energy of this new isomer Conf. 8 10.6 29.8 11.4 III_C2 a conformational analysis was also performed (see Conf. 9 17.1 10.3 2.5 Supporting Information). The two most stable confor- Conf. 10 10.9 27.4 4.3 mations are 2 and 3 (Table 1 and Figure 10). Conformation a 3 is 2.7 kcal mol-1 higher in energy than conformation 2. This conformation has a relative Gibbs energy of -9.8 kcal Nevertheless, conformation 3 has the appropriate geomet- mol-1 within reaction profile in Figure 8. rical disposition of the free phosphine arm to undertake The Gibbs energy profile for pathway C is represented in the bromide by phosphine ligand substitution process. Figure 8. The transition state for the first step, TS_II_C1 This means that although this conformation is higher in (Figure 9), is located at -1.2 kcal mol-1, with a relative Gibbs energy, it must be involved in this reaction path. Therefore, energy barrier of 17.1 kcal mol-1. The intermediate formed, this conformation is the one included in the reaction pro- III_C1 has a relative Gibbs energy of -9.8 kcal mol-1. From file (Figure 8). 5 Conformations ΔΔGsolv ΔΔGsolv ΔΔGsolv III_D1 III_D1’ III_D2 Conf. 1 4.7 8.4 4.6 Conf. 2 5.2 16.6 6.1 Conf. 3 10.3 7.0 0.1 Conf. 4 0.0a 8.3 7.9 Conf. 5 1.2 7.6 1.3 Conf. 6 0.5 16.8 -0.6 b Conf. 7 2.6 22.8 2.0 Conf. 8 19.9 25.4 13.6 Conf. 9 19.1 17.5 14.1 Conf. 10 9.7 13.5 7.5 aThis conformation has a relative energy of -10.5 kcal mol- 1within reaction profile in pathway D (Figure 11). b This conformation has a relative energy of 3.4 kcal mol-1 within reaction profile in pathway D (Figure 11). Figure 10. Optimized geometries for conformations of in- termediate III_C2: (a) 2 and (b) 3. The isomerization evolves giving rise to intermediate III_C2, located at -9.3 kcal mol-1 very close in energy to the preceding intermediate, III_C1. Next step is the association of the phosphine and replacement of the halide through transition state TS_II_C2 (located at -3.0 kcal mol-1; Figure 8). This step has a relative Gibbs energy barrier of 6.3 kcal mol-1. The intermediate formed in this step is analogous to that obtained in pathway B, III_B1, with the phosphine di- coordinated and the phenyl and NH3 ligands in cis posi- tion. This point on the profile is analogous to that pre- sented for pathway B, so structures were equally named. Figure 11: Gibbs energy profile involving phosphine disso- - Pathway D ciation of P2 (Pathway D) in 1-4 dioxane (kcal mol-1). In this pathway the base plays a double role in the reaction, The Gibbs energy profile for this pathway is shown in Fig- similarly to pathway A. The complete ligand substitution ure 11. The transition state for the first step, substitution of process occurs through three consecutive replacements: (i) the phosphine P2 by t-BuO⁻, (from (t-BuONa)4) TS_II_D1 the phosphine arm P2 by the base, t-BuO⁻, (ii) bromide lig- (Figure 12), is located at 16.5 kcal mol-1, with a relative Gibbs and by the incoming amine and finally (iii) the phosphine energy barrier of 34.8 kcal mol-1. The intermediate formed, recovers the coordination site by replacing the base t-BuO⁻ III_D1, has a relative energy of 10.5 kcal mol-1 and corre- along with the deprotonation of the coordinated amine. sponds to conformation 3 (Table 2). For the mechanistic As in the previous case, the replacement of the phosphine analysis only the most stable conformation was considered arm by the base generates an intermediate with a mono- (it does not modify the conclusions of the work since this dentate phosphine ligand that requires a conformational pathway is discarded). Next step corresponds to the substi- analysis to evaluate the most feasible intermediate. Like in tution of the bromide by ammonia, with a Gibbs energy for the previous pathway (Scheme 2), two different isomers TS_II_D2 of 18.2 kcal mol-1. A conformational analysis was can be formed depending on which is the substituted arm also performed for this intermediate, III_D2, with the most of the phosphine. Releasing phosphine P1 is more energetic stable conformation located at 3.4 kcal mol-1 (see Support- than P2, thus, the later was the only one considered. The ing Information). The last step corresponds to the replace- results for the conformational analysis are gathered in Ta- ment of the t-BuO⁻ by the phosphine arm, concomitantly ble 2 (see Supporting Information). to the proton transfer from the coordinated NH3 ligand to the releasing base. This step goes through TS_II_D3 with a relative Gibbs energy barrier of 2.9 kcal mol-1 (Figure 12). Table 2: Gibbs relative energies (kcal mol-1) for conformers The intermediate formed, IV_base_A (-15.2 kcal mol-1), re- of intermediates III_D1, III_D1’ and III_D2. covers the coordination of the biphosphine. Such an 6 intermediate is common for all analysed pathways. This is TS_IV by 3.1 kcal mol-1. Both computed paths give rise to the highest energy pathway among all considered ones. the formation of the same intermediate V. Figure 13: Energy Gibbs profile for the oxidative addition in 1-4 dioxane (kcal mol-1). Reaction Mechanism Proposed In the previous section several pathways for the Pd-Josi- phos catalyzed Buchwald-Hartwig amination of arylbro- mide using ammonia were evaluated. In this section we discuss these results. The first and last steps, oxidative addition and reductive elimination, are common to any coupling reaction.5,63 Both steps are concerted. Since Josiphos is an asymmetric phos- phine the oxidative addition may give rise to two different isomers, however, one of them, intermediate II is clearly kinetically and thermodynamically favoured. The oxidative addition has a rather low energy barrier as expected for a Figure 12: Optimized geometries for: (a) TS_II_D1, (b) strong electron-donating and steric bulky ligand as Josi- TS_II_D2 and (c) TS_II_D3. Distances in Å. phos. The reductive elimination step is rate determining, in agreement with other computational studies 37,39,39,40 and Reductive Elimination experiment.17,64 The last step of the whole mechanism is the reductive elim- For the ligand substitution process four different alterna- ination. It takes places from IV intermediate having NH2- tives were considered, pathways A, B, C and D. The two and Ph ligands in cis position. It is located at -12.1 kcal mol- first pathways proceed without dissociation of the phos- 1; calculation performed without additional species in the phine, whereas the last two involve the dissociation of one model (Figure 13). As well as the oxidative addition, the re- of the phosphine arms of the bidentated ligand. The rela- ductive elimination is common for the four evaluated path- tive energy barriers for the step after the oxidative addition ways (A, B, C and D). The Gibbs energy barrier for reduc- are 28.5, 20.8, 17.1 and 34.8 kcal mol-1 for pathways A, B, C tive elimination, through the transition state TS_IV, is 17.6 and D, respectively. Pathways B and C are the most feasible kcal mol-1. The reductive elimination takes place through a ones, with the later 3,7 kcal mol-1 lower in energy than the concerted step. The formed intermediate V is located at - former. Both pathways are analogous, in the sense that the 34.6 kcal mol-1. This intermediate contains the final prod- amine replaces the bromide ligand, thus t-BuO- only acts uct of the catalytic cycle for the Buchwald-Hartwig amina- as a base. The difference between B and C comes from the tion coordinated to the Pd center. Replacement of the fact that in C the phosphine dissociates one of the arms product by the arylbromide reactant closes the catalytic cy- thus offering a new coordination site. In fact, the relative cle. Gibbs energy barrier for any of these two paths is lower than that for reductive elimination. Therefore, according For the sake of completeness, the reductive elimination to these results both pathways can be operative during the was also calculated for the other possible isomer where the process, though pathway C is the most favoured one. Ph an NH2⁻ ligands interchange their positions, interme- diate IV_op. This intermediate is 3.4 kcal mol-1 higher in A general scheme for the catalytic cycle is shown in Figure energy than intermediate IV. The relative Gibbs energy 14. It can be described by (i) oxidative addition, (ii) replace- barrier for this step, TS_IV_op, is also higher than that for ment of a phosphine arm by the ammonia ligand, (iii) isomerization of ligands NH 3 and Br- respect to the aryl 7 group and replacement of the halide by the P2 phosphine, works, the reductive elimination has the highest Gibbs en- (iv) deprotonation of coordinated amine by the base (t- ergy barrier. BuO⁻), and (v) reductive elimination. The direct replace- For the sake of completeness, we also evaluated the possi- ment of Br- by NH3 without releasing any of the chelate bility for the comproportionation between the active cata- phosphine arms is also accessible (Figure 14 dashed arrow). lyst Pd0, and the precatalyst PdIICl2 intermediates to form the dimeric Pd(I) complex (Scheme 3). The presence of highly reactive Pd0 active species may promote the for- mation of other bimetallic species that can favor the pro- cess, or be detrimental, depending on the condi- tions.65,66,67,68 This reaction competes with the first step of the catalytic cycle, the oxidative addition step. For the for- mation of the dimeric complex we assumed that both Pd centers have a coordinated Josiphos chelated ligand. Scheme 3: General scheme for Pd(0) + Pd(II) compropor- tionation. The dimer formation has a ΔG of 13.0 kcal mol-1, which in- dicates that the dimer is less stable than the separated re- Figure 14: Catalytic cycle proposed for the for Buchwald- actants. The analysis of the structure shows that the com- Hartwig amination using a chelated Pd-complex and am- plex has not the structural characteristics expected for a monia; (P1-P2 = Josiphos). Pd(I)-Pd(I) dimer. The distance between both Pd atoms is The mechanistic proposal for a Pd-catalyst with mono- 4.089 Å, much longer than the expected distance around 3 phosphine ligand shows that for the ligand substitution Å. Moreover, the geometry around one of the Pd centers is process (see Figure 2), the catalyst substitutes the bromide square planar whereas the other is tetrahedral. This geo- ligand by the coordination of the amine along with the sub- metrical arrangement around the metallic centers indicate sequent deprotonation.37 In the case of the Pd-catalyst with that the bidentated complex corresponds to a Pd(II)-Pd(0) the Josiphos chelate ligand, the mechanistic proposal in- dimer. Several attempts to obtain the Pd(I)-Pd(I) dimer troduces some differences. Although the analogous mech- were performed, but when releasing all the fixed parame- anism is feasible, in the preferred pathway the amine re- ters the geometry converged to the one shown in Figure 15. places a phosphine arm instead of the bromide. Then, after Similar behaviour was found for the dimer with bromide as an isomerization the phosphine arm replaces the bromide bridging ligands (see Figure S7). Therefore, the formation to generate an intermediate ready for the reductive elimi- of Pd(I)-Pd(I) dimeric species can be discarded when che- nation. lating Josiphos phosphine is used as ligand. For the ligand substitution process one can observe that replacing Br⁻ by NH3 is more feasible than its replacement by t-BuO-. Moreover, the substitution of Br ⁻ by NH3 is also more favorable than the replacement of t-BuO⁻ by NH3 (as found for intermediate III_D1 in pathway D). These factors together are behind the fact that the base, t-BuO⁻, is acting only as a base, and not as a ligand. These results are in line with previous suggestions that one of the arms of the BINAP phosphine is released during the reaction;39 the au- thors were examining the relative energy of the feasible in- termediates involved in the reaction without calculating the barriers; in those terms such proposal could be feasible Figure 15: Optimized geometry for the Pd-Josiphos dimer. although they did not exclude other possible pathways. In- Distances in Å. deed, the present calculations including the energy barri- ers for all the ligand substitution steps shows that the CONCLUSIONS phosphine does not remains coordinated along the mech- anism. These results are somehow related to the conclu- The C-N coupling between arylbromide and ammonia cat- sions reported by Baik33 and Ma41 where they found for the alysed by Pd-Josiphos chelate complex is analyzed by case of the Buchwald phosphine, such ligand also gener- means of DFT calculations. A general scheme for the cata- ates a coordination site along the reaction pathway to be lytic cycle can be described as follows (Figure 14): (i) oxida- occupied by the amine. Moreover, in agreement with these tive addition, (ii) replacement of a phosphine arm by the ammonia ligand, (iii) cis-trans isomerization of the ligands NH3 and Br- respect to the aryl group along with 8 replacement of the halide ligand by the phosphine arm, Gibbs energies in 1,4-dioxane were calculated at 298 K. A (iv) deprotonation of coordinated amine by the base (t- correction of 1.9 kcal mol-1 was applied to all Gibbs energies BuO-), and (v) reductive elimination. The direct replace- calculated to change the standard state from the gas phase ment of Br- by NH3 is slightly higher in energy but accessi- (1 bar) to solution (1 M).74 Thermal contributions to the ble. Gibbs energies were corrected by employing the approxi- The oxidative addition and reductive elimination steps are mation described by Grimme75 where entropic terms for concerted.37,39 The oxidative addition shows a rather low frequencies below a cut-off (100 cm-1), were calculated us- energy barrier as expected for a bulky and electron-donat- ing the free-rotor approximation. The GoodVibes program ing ligand as Josiphos. The reductive elimination step, developed by Paton and Funes-Ardoiz was employed to in- however, shows the highest relative energy barrier for the troduce these corrections.76 process. These conclusions are in agreement with other ex- The system selected for the theoretical study includes the perimental 17,64 and computational studies.37,39 The possi- bidentate (Josiphos) coordinated to Pd catalyst, PhBr and bility for the comproportionation between Pd(0) and NH3 as substrates and (t-BuONa)4 as base; the model for Pd(II) species was evaluated obtaining that it is unfeasible the base was a tetrameric form considering the non-polar for the Pd-Josiphos chelating system. environment of the reaction, as illustrated in the Figure For the ligand substitution process four different path- 16.33, ,77,78 These species were selected according to experi- ways, A, B, C and D were evaluated: C and D involve disso- ments made by Hartwig and co-workers.17,18,64 We took the ciation of a phosphine arm, whereas for A and B the Josi- X-ray crystallographic structure of Josiphos ligand coordi- phos remains fully coordinated to Pd center. The two fea- nated to Pd64 as starting point for optimizing the geome- sible pathways B and C, both entail the replacement of the tries. Josiphos is not symmetric with P1 and P2 bearing cy- halide by the amine. The most favourable pathway, C, in- clohexyls and isobutyls, respectively (Figure 16). volves the dissociation of a phosphine arm along the pro- cess. A conformational analysis of the intermediate with open chelate is required to properly evaluate this path. Regarding substitution patterns, replacement of Br⁻ by NH3 at the coordination sphere of Pd(Josiphos) is more feasible than its replacement by t-BuO-. The substitution of Br⁻ by NH3 is also more favourable than the replacement of t-BuO ⁻ by NH3. Thus, the t-BuO- does not act as a lig- and in this process, acting only as a base. The ligand sub- stitution process follows a similar trend for mono- or bi- dentated phosphine catalysts. Overall, we analyzed the reaction mechanism for the Pd- Josiphos catalyzed C-N coupling of arylbromide with NH3 identifying the role of the chelating phosphine and the base providing useful information for rational design of new chelating ligands. Figure 16. (a) Optimized structure for Pd(Josiphos)(PhBr), EXPERIMENTAL SECTION intermediate I. (b) Scheme of the intermediate I. (c) Sche- matic illustration of base as tetrameric form (t-BuONa)4 , Computational Data. Calculations were performed using cluster-t-BuO, and [(t-BuO)3BrNa4], cluster-Br. the M06 functional69 with an ultrafine grid, as imple- mented in Gaussian 09.70 The Pd atom was described using the scalar relativistic Stuttgart−Dresden SDD pseudopo- Pathways considering dissociation of one of the phosphine tential and its associated double-ζ basis set, complemented arms were also considered. To obtain a proper confor- with a set off functions.71 The 6-311G(d,p) basis set was used mation of the catalyst we performed a conformational for the rest of atoms. The structures of the reactants, prod- study on such intermediates. For such analysis classical ucts, intermediates and transition states were optimized in MD simulations were performed at constant temperature 1,4-dioxane solvent (ε=2.25), described by the SMD polar- using Amber 16.79 The temperature was set at 1000 K to en- izable continuum model.72 The nature of the stationary sure a wide exploration of the conformational space. The points was confirmed by frequency analysis. Connections scheme developed by Merz80 to obtain force field parame- between the transition states and the minima were ters compatible with the Amber force field79 based on the checked by following the IRC and subsequent geometry Seminario method81 was employed. Calculations were per- optimization until the corresponding minima. Cartesian formed under solvent-free conditions. A 1 fs time step was coordinates for the supporting information were generated used to integrate the equations of motion, for a total sim- by EsiGen software.73 ulation time of 10 ns. Coordinates were saved every 1000 steps, for a total of 10000 structures. The k-means 9 clustering method82 was applied to those structures ob- 71, 6192–6203. taining ten different clusters. The most representative (9) Nayal, O. S.; Bhatt, V.; Sharma, S.; Kumar, N. structure for each of the clusters was subsequently opti- Chemoselective Reductive Amination of Carbonyl mized at the same DFT level to check the feasibility of Compounds for the Synthesis of Tertiary Amines Using these conformers and their relative Gibbs energy. SnCl2·2H2O/PMHS/MeOH. J. Org. Chem. 2015, 80, 5912–5918. ASSOCIATED CONTENT (10) Shin, K.; Kim, H.; Chang, S. Transition-Metal-Catalyzed C-N Bond Forming Reactions Using Organic Azides as Supporting Information. Figures of relevant structures; in- the Nitrogen Source: A Journey for the Mild and Versatile formation about a transition state search; cartesian coordi- C-H Amination. Acc. Chem. Res. 2015, 48, 1040–1052. nates. This material is available free of charge via the Internet (11) Ruiz-Castillo, P.; Buchwald, S. L. Applications of at http://pubs.acs.org.” Palladium-Catalyzed C−N Cross-Coupling Reactions. Chem. Rev. 2016, 116, 12564–12649. AUTHOR INFORMATION (12) Van der Vlugt, J. I. Advances in Selective Activation and Corresponding Author Application of Ammonia in Homogeneous Catalysis. Chem. Soc. Rev. 2010, 39, 2302–2322. Agustí Lledós − Departament de Química, Universitat Autònoma de Barcelona and Centro de Innovacioń en Quí- (13) Klinkenberg, J. L.; Hartwig, J. F. Catalytic mica Avanzada (ORFEO-CINQA), 08193 Cerdanyola del Va- Organometallic Reactions of Ammonia. Angew. Chem., llès, Catalonia, Spain; Int. Ed. 2011, 50, 86–95. orcid.org/0000-0001-7909-422X; (14) Aubin, Y.; Fischmeister, C.; Thomas, C. M.; Renaud, J. L. Email: agusti@klingon.uab.es Direct Amination of Aryl Halides with Ammonia. Chem. Gregori Ujaque − Departament de Química, Universitat Soc. Rev. 2010, 39, 4130–4145. Autònoma de Barcelona and Centro de Innovacioń en Quí- (15) Schranck, J.; Tlili, A. Transition-Metal-Catalyzed mica Avanzada (ORFEO-CINQA), 08193 Cerdanyola del Va- Monoarylation of Ammonia. ACS Catal. 2018, 8, 405– llès, Catalonia, Spain; 418. orcid.org/0000-0001-5896-9998; (16) Streiff, S.; Jérôme, F. Hydroamination of Non-Activated Email: gregori.ujaque@uab.cat Alkenes with Ammonia: A Holy Grail in Catalysis. Chem. Soc. Rev. 2021. ACKNOWLEDGMENT (17) Vo, G. D.; Hartwig, J. F. 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