Computational study of the copper-free Sonogashira cross-coupling reaction : shortcuts in the mechanism

The sec-butylammonium salt catalysed oxidative addition of phenyl bromide to tris(triphenylphosphane)palladium and reaction of phenylacetylene with cis-Pd(PPh3)2(Ph)Br were modelled using DFT B97D/cc-pVDZ method to study the mechanism of the copper-free Sonogashira cross-coupling reaction. sec-Butylammonium bromide influences the oxidative addition by coordinating with palladium catalyst and the resulting product is trans-Pd(PPh3)2(Ph)Br, not the corresponding cis-compound, which is formed in the absence of salt. The transition-state energy of this oxidative addition mechanism is very close to the previously reported biligated oxidative addition pathway. Reaction of acetylene with cis-Pd(PPh3)2(Ph)Br can lead to either a transor a cis-Pd(PPh3)2(CCPh)Ph complex, while only the latter is capable of undergoing reductive elimination.


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The Sonogashira cross-coupling reaction takes place between aryl halide (ArX) and terminal acetylene, catalysed by a zerovalent palladium catalyst to produce diyne (see Fig. 1).
It belongs to the family of palladium-catalysed crosscoupling reactions, which have been a valuable tool for organic synthesis since their discovery [1][2][3].In a typical Sonogashira cross-coupling reaction, copper is used as a co-catalyst, but a series of copper-free Sonogashira reactions have been developed to suppress homocoupling of the terminal acetylenes [4,5].The mechanism of the catalytic cycle has not been extensively studied, although * Corresponding author, Lsikk@ut.eesome computational papers on the full catalytic cycle have been published [6][7][8][9][10][11].The reaction mechanism is similar to other palladium-catalysed cross-coupling reactions and it consists of oxidative addition, cis-trans isomerization, deprotonation (also called alkynylation), and reductive eliminantion steps.Oxidative addition (reaction of aryl halide with a zerovalent palladium catalyst) is often described as a rate-limiting step, and numerous papers are dedicated to the experimental and theoretical investigations of its kinetics and mechanism [12][13][14][15].Many authors have demonstrated that halide anions in the reaction mixture accelerate the oxidative addition [16][17][18][19], but our recent computational study in dichloromethane solution revealed that halide anions alone are not responsible for the increase of the reaction rate [9].These results are backed up by the experimental work of Barrios-Landeros et al., who showed that both the halide ion and the corresponding cation of organic base play an important role in the reaction [20].The product of oxidative addition, cis-PdL 2 ArX, can isomerize to the corresponding trans-complex.This reaction is usually fast and many reaction mechanisms are possible [21,22].
The deprotonation step in the Sonogashira crosscoupling is a reaction between terminal acetylene and the product of oxidative addition and results in PdL 2 Ar(C≡≡CAr').The deprotonation step, starting from the trans-PdL 2 ArX complex, is usually accepted as the dominant reaction pathway [4,[23][24][25]], but at the same time a similar reaction can take place with the corresponding cis-isomer, which is especially important for chelating ligands, where the formation of trans-PdL 2 ArX is not possible [15].The last step of the catalytic cycle is reductive elimination, where a new carbon-carbon bond is formed and the catalyst is regenerated.Aside from the traditional mechanism described in this paper, an alternative carbopalladation pathway was described by Ljungdahl and coworkers [26].
The aim of the current study was to model computationally some "non-classical" and less-studied pathways in the copper-free Sonogashira cross-coupling reaction.First, the oxidative addition step, co-catalysed by secbutylammonium bromide, was studied to test the reaction pathway proposed by Barrios-Landeros et al. [20].Secondly, we studied two different mechanisms of the deprotonation step starting from cis-PdL 2 ArX to elucidate their feasibility relative to the earlier studied isomerization of cis-PdL 2 ArX to trans-PdL 2 ArX and the following deprotonation [9].

THEORETICAL MODEL
The study of the copper-free Sonogashira cross-coupling reaction was carried out by determining the structures corresponding to ground states and transition states on the reaction energy hypersurfaces.
The copper-free Sonogashira coupling between phenyl bromide (PhBr) and phenylacetylene (PhC≡≡CH) was modelled, where tetrakis(triphenylphosphano)palladium (Pd(PPh 3 ) 4 ) was used as a catalyst and sec-butylamine (sec-BuNH 2 ) as a base.Being small enough for computational study, these reagents are used in the synthesis of disubstituted acetylenes.As sec-BuNH 2 has two enantiomers commonly used as a racemic mixture, we performed the calculations using S-sec-BuNH 2 in order to minimize the computational cost.
All calculations were performed with Gaussian 09 program package [27] using density functional theory (DFT) with hybrid B97D functional [28,29] and the cc-pVDZ basis set [30].In the case of palladium, Stuttgart-Dresden effective core potentials with accompanying basis sets were used (obtained from EMSL Basis Set Exchange) [31,32].Harmonic frequency analysis was used to confirm correspondence of the found structures either to minima (number of imaginary frequencies equals zero) or transition states (number of imaginary frequencies equals one).Unscaled frequencies from vibrational analysis were also used to get enthalpies and free energies in the standard state (1 atm and 298.15 K).In the following discussion enthalpies are used to characterize the energies of stationary points found on the potential energy surface (PES), as computational methods are less accurate for predicting entropies and free energies than enthalpies [33].Intrinsic reaction coordinate (IRC) analysis was used to verify that the obtained transition state connects reactants and products [34,35].All geometry optimizations and frequency calculations were performed in dichloromethane (DCM) using the continuum solvation model SMD [36].Dichloromethane was chosen as a solvent, as it is widely used in both NMR measurements and synthetic procedures.More importantly, DCM is a weakly coordinating solvent, thus, non-inclusion of specific solvent effects is justified.The free energy values were corrected to 1 mol/L standard state [37].

Oxidative addition
In our previous paper, we reported four different oxidative addition pathways (monoligated, biligated, anion-assisted, and base-assisted mechanisms), among which the biligated pathway had the lowest-energy transition state (∆H = 29.1 kcal/mol, ∆G = 28.2kcal/mol, relative to the starting compounds) [9].The anion-assisted oxidative addition pathway is much higher in energy (mainly due to the separation of charges in apolar solvent), and a further investigation of the halide ion influence on the oxidative addition was required.The mechanism proposed here is based on the experimental work by Barrios-Landeros et al. [20].
As noted in our previous paper, the active palladium catalyst is Pd(PPh 3 ) 3 (1, Scheme 1), which undergoes the oxidative addition through a series of association and dissociation steps [9].
The first step is the coordination of sec-butylammonium bromide (which is a product of the Sonogashira cross-coupling reaction) to palladium complex 1.This reaction is exothermic (∆H = -9.5 kcal/mol, ∆G = 1.3 kcal/mol), and the Br-Pd distance in the resulting complex 2 is 4.592 Å.The subsequent ligand dissociation and the formation of trigonal planar complex 3 decreases the Br-Pd bond length to 2.893 Å, which is mainly due to the steric effects of the ligands.The bromine atom lies slightly above the P-Pd-P plane (by 14.4°) and the P-Pd-P angle is 132.9°.The subsequent ligand dissociation gives rise to complex 4, where the phosphane ligand and Br are in the trans position (P-Pd-Br angle is 170.5°) and one hydrogen atom of the amino group of secbutylammonium ion interacts with palladium (Pd-H distance is 2.817 Å), while the other hydrogen atom is Scheme 1. Salt-assisted mechanism of oxidative addition.Free energies and enthalpies (in square brackets) are in kcal/mol, relative to starting compounds.directed toward bromine atom (Br-H distance is 2.336 Å).Coordination of phenyl bromide to 4 results in complex 5, where bromine atom, originating from ammonium salt, is located in the trans position relative to phenyl bromide, and sec-butylammonium cation is acting as a bridge between the two bromine atoms.Palladium atom interacts with carbons 1 and 2 of phenyl bromide (Pd-C distances are 2.126 Å and 2.241 Å, respectively).This interaction increases the Br-C bond distance in phenyl bromide (2.056 Å in complex 5, 1.935 Å in free phenyl bromide).The geometry of complex 4 was confirmed by the removal of phenyl bromide from complex 5 and the subsequent geometry optimization.Structure 5 is followed by transition state 6, which is by 28.8 kcal/mol higher in free energy and by 31.2 kcal/mol higher in enthalpy than the starting compounds.The imaginary frequency of the transition state 6 corresponds to the increase in the C-Br bond length, while the Pd-C bond length is 2.014 Å. Transition state 6 is followed by complex 7, which can be described as a trans-PdL(Ph)Br complex with secbutylammonium bromide.In this complex, the phenyl group and bromine atom are in the trans position, while the bromide ion of the ammonium salt is above the C-Pd-P plane (Pd-Br distance is 4.360 Å), and the secbutylammonium cation acts as a bridge between the two bromine atoms.The subsequent addition of phosphane ligand results in a trans-PdL 2 (Ph)Br complex with secbutylammonium bromide (8), which gives the end product of oxidative addition (trans-PdL 2 (Ph)Br, 9) after the dissociation of the ammonium salt.One could argue that the dissociation of the ammonium salt from complex 7 would also be a viable pathway, but as we were unable to find a minimum for the trans-PdL(Ph)Br complex (all geometry optimizations resulted in the cis-PdL(Ph)Br complex), this reaction route was ruled out.
Complex 3 can form cis-PdL 2 (H)(Br) (3a) through the loss of sec-butylamine.Barrios-Landeros et al. showed that in the case of P t Bu 3 ligands, complex 3a is more reactive toward phenyl bromide than Pd(P t Bu 3 ) 2 [20].Contrary to that, we were unable to find oxidative-addition pathways involving complex 3a.The transition state energies of the previously reported biligated oxidative addition pathway [9] and the saltcatalysed pathway described here are very close (enthalpies 29.1 and 31.2 kcal/mol; free energies 28.2 and 28.8 kcal/mol, respectively, relative to starting compounds).The difference is so small that on the basis of these calculations it is very hard to correctly evaluate which of these pathways is energetically favoured.
It is important to note that in the product of oxidative addition (complex 9) bromine atom and phenyl group are in the trans position.This suggests that after a few catalytic cycles, when enough ammonium salt is produced in the reaction (see Fig. 1), the copper-free Sonogashira cross-coupling can switch to the salt-catalysed oxidative addition pathway and, thus, omit the cis-trans isomerization step.

Deprotonation
The product of oxidative addition reacts with alkyne in the presence of base resulting in the PdL 2 (PhCC)Ph complex.The base is required to deprotonate the alkyne and is sometimes used as a solvent in the copper-free Sonogashira reactions [5].The isomerization of the oxidative addition product cis-Pd(PPh 3 ) 2 (Ph)Br to trans-Pd(PPh 3 ) 2 (Ph)Br is usually very fast [38] and therefore, the trans-complex is generally accepted as the starting point of the deprotonation step.On the other hand, bidentate ligands, which cannot form this type of transcomplexes, have been successfully used in the copperfree Sonogashira reaction [39] and the reaction of cis-Pd(PPh 3 ) 2 (Ph)Br with alkyne should be considered as a possible reaction pathway.In the next section of this article, we report the computationally obtained reaction mechanisms for deprotonation that starts from the cis-Pd(PPh 3 ) 2 (Ph)Br complex.These are alternative routes to the mechanism of deprotonation reaction described in our previous article [9].
The first deprotonation mechanism of the cis-Pd(PPh 3 ) 2 (Ph)Br complex (Scheme 2, I) starts with the dissociation of the phosphane ligand in the trans position to the phenyl group and the formation of the cis-Pd(PPh 3 )(Ph)Br complex (Scheme 2, 11).The consecutive coordination of phenylacetylene and sec-butylamine to 11 are both exothermic and give rise to complexes 12 and 13, respectively, where the triple bond of phenylacetylene is perpendicular to the Br-Pd-P plane.The imaginary frequency of the transition state of the trans-deprotonation step ( 14) corresponds to the elongation of the C-H bond of the acetylenic proton.This transition state leads to structure (15), which, in turn, forms the anionic trans-Pd(PPh 3 )(CCPh)PhBr -complex ( 16) after the dissociation of the protonated base.Due to the formation of charged species, this reaction is endothermic (∆∆H = 23.1 kcal/mol and ∆∆G = 11.9 kcal/mol).Complex 16 can release bromide ion to generate sec-butylammonium bromide and the monoligated species 17, which can form the biligated complex 18 as the end product of trans-deprotonation pathway.This deprotonation mechanism leads to the palladium complex where the phenyl-and phenylacetylenic groups are in the trans position.A previous mechanistic study showed that this type of complex is unable to undergo reductive elimina- tion and the isomerization to the corresponding ciscomplex is very slow [40].On the basis of these results we can treat this deprotonation mechanism as "unproductive" in the overall reaction scheme, leading to a reduced concentration of the active palladium catalyst.
The cis-deprotonation mechanism of the cis-Pd(PPh 3 ) 2 (Ph)Br complex (Scheme 2, II) starts with the dissociation of the triphenylphosphane ligand in the cis position to the phenyl group from complex 10 and the formation of the cis-Pd(PPh 3 )(Ph)Br complex (Scheme 2, 19).We can see that the ligand dissociation from the trans position to the phenyl group is energetically favoured (∆∆H = 29.3kcal/mol and ∆∆H = 47.5 kcal/mol, respectively) compared to the dissociation from the cis position (Scheme 2, 11).This large difference in the reaction enthalpies can be attributed to the larger trans-effect of the phenyl group compared to bromine atom.The cis-deprotonation mechanism proceeds similarly to the previously described transdeprotonation mechanism: the consecutive addition of phenylacetylene and base results in the formation of complexes 20 and 21.Similarly to 14, the imaginary frequency of transition state 22 corresponds to the elongation of the C-H bond of the acetylenic proton.Transition state 22 leads to the formation of the cis-Pd(PPh 3 )(CCPh)PhBr -complex (23).The dissociation of the sec-butylammonium cation from complex 23 leads to cis-Pd(PPh 3 )(CCPh)PhBr - (24), where the phenyl-and phenylacetylenic groups are in the cis position.Similarly to 16, the bromine atom can be substituted by triphenylphosphane ligand to generate cis-Pd(PPh 3 ) 2 (CCPh)Ph (26) through the monoligated intermediate 25.The end product of the cis-deprotonation mechanism (26) is the starting point for the lowestenergy reductive elimination pathway leading to the formation of diphenylacetylene and the regeneration of the catalyst [9].
The deprotonation mechanism starting with the substitution of bromine atom in the cis-Pd(PPh 3 ) 2 (Ph)Br complex (10) to phenylacetylene was also investigated.However, the transition state corresponding to the deprotonation of alkyne in this complex was not found.
Comparing these two deprotonation pathways of the cis-Pd(PPh 3 ) 2 (Ph)Br complex, the cis-and transdeprotonation mechanisms may seem to occur at the same rate as the energies of transition states 14 and 22 are very close.On the other hand, the first intermediate in the cis-deprotonation pathway (19) has much higher energy than the transition states, indicating that the trans-deprotonation mechanism is favoured over the cisdeprotonation mechanism.It should be kept in mind that the trans-deprotonation pathway leads to the formation of trans-Pd(PPh 3 ) 2 (CCPh)Ph (18), which cannot undergo reductive elimination.Moreover, the product of transition state 14 is higher in energy than the reactants, indicating that the trans-deprotonation pathway is shifted toward the formation of reactants.
The computational modelling of these two deprotonation pathways suggests that although a reaction between phenylacetylene and cis-Pd(PPh 3 )(Ph)Br is possible, the previously reported isomerization to trans-Pd(PPh 3 )(Ph)Br and the subsequent reaction with phenylacetylene are energetically favoured [9].However, the studied mechanisms may be important in the case of chelating ligands, where the formation of a trans-complex is impossible.

Complete catalytic cycle
By combining the computational results described here with our previous findings [9], a general mechanism for the copper-free Sonogashira cross-coupling reaction can be constructed.The full catalytic cycle starts with the oxidative addition of aryl halide to the palladium catalyst Pd(PPh 3 ) 3 , which can result in either a cis-or a trans-complex (Scheme 3, routes A and A′, respectively).The isomerization of cis-Pd(PPh 3 ) 2 (Ph)Br to the corresponding trans-Pd(PPh 3 ) 2 (Ph)Br is also possible (Scheme 3, B) as both of these isomers can react with phenylacetylene to produce cis-Pd(PPh 3 ) 2 (CCPh)Ph (Scheme 3, routes C and C′, respectively).The formation of the trans-Pd(PPh 3 ) 2 (CCPh)Ph complex is possible from cis-Scheme 3. Mechanism of the copper-free Sonogashira crosscoupling reaction.
Pd(PPh 3 ) 2 (Ph)Br (Scheme 3, E).The last step of the catalytic cycle is reductive elimination (Scheme 3, D), where diphenylacetylene is formed and the catalyst is regenerated.

CONCLUSIONS
The mechanism of the copper-free Sonogashira crosscoupling reaction is a complicated system of reaction pathways.The energetically most favoured reaction mechanism is composed of four steps: oxidative addition, cis-trans isomerization, deprotonation, and reductive elimination (A, B, C, and D in Scheme 3).On the other hand, the oxidative addition, which leads directly to the trans-product, and the deprotonation step starting from the cis-Pd(PPh 3 ) 2 (Ph)Br complex (A′ and C′, respectively, in Scheme 3) are energetically close to the lowest energy pathway.These pathways can be described as "shortcuts in the reaction", as they reduce the number of reaction steps in the catalytic cycle to three and all these reaction pathways can be of importance in experimental conditions.

Scheme 2 .
Scheme 2. Mechanisms of trans-(I) and cis-(II) deprotonation.Free energies and enthalpies (in square brackets) are in kcal/mol, relative to the starting compounds.