MW-Promoted Cu(I)-Catalyzed P–C Coupling Reactions without the Addition of Conventional Ligands; an Experimental and a Theoretical Study

: An experimental and a theoretical study on the so far less investigated Cu(I) salt-catalyzed Hirao reaction of iodobenzene and diarylphosphine oxides (DAPOs) revealed that Cu(I)Br or Cu(I)Cl is the most efﬁcient catalyst under microwave irradiation. The optimum conditions included 165 ◦ C and a 1:2 molar ratio for DAPOs and triethylamine. The possible ligations of Cu(I) were studied in detail. Bisligated P—Cu(I)—P ( A ), P—Cu(I)—N ( B ) and N—Cu(I)—N ( C ) complexes were considered as the catalysts. Calculations on the mechanism suggested that complexes A and B may catalyze the P–C coupling, but the latter one is more advantageous both according to experiments and calculations pointing out the Cu(I) → Cu(III) conversion in the oxidative addition step. The P–C coupling cannot take place with PhBr, as in this case, the catalyst complex cannot be regenerated.

Intensive studies involving experiments and calculations explored the fine mechanism of the Pd-and Ni-catalyzed variations. In contrast to the Pd(II) → Pd(0) conversion [9,10] observed for the Pd(OAc) 2 -catalyzed option, a Ni(II) → Ni(IV) transition was substantiated for the NiCl 2 -promoted case [11,12]. This was a brand new observation [13].
Cu-catalysis offers cheaper and hence a more practical realization of P-C coupling reactions as compared to the use of Pd-or Ni-catalysts, but this option has only been studied occasionally. The first Cu-catalyzed Hirao reaction of aryl halides and dibutyl phosphite using CuI as the precursor was carried out by Buchwald et al. [14]. During the syntheses, DMEDA proved to be a useful N-ligand, that was also applied in further cases [15][16][17]. Other N-ligands were also tested in the "CuI-catalyzed" coupling reactions: Beletskaya et al. found 2,2 -bipyridine and 1,10-phenanthroline to be the best ligands in the reaction of aryl iodides and diethyl phosphite, but good results were obtained in the presence of TMEDA, 1-methyl-1H-imidazole [18], N-methylpyrrolidine-2-carboxamide [19], proline and pipecolic acid [20], (S)-α-phenylethylamine [21,22], or 1-pyrrodinylphosphonic acid monophenyl ester as well [23]. It is noted that the reactivity of aryl bromides was far behind that of the corresponding iodides, but when the bromoarenes were pre-reacted with Table 1. Optimization of the P-C coupling reaction of iodobenzene and diphenylphosphine oxide in the presence of CuI.  In the next stage, different Cu + precursors were tested in the model reaction selected Applying 20% of CuBr as the catalyst at 165 °C for 3 h at a 1:1 ratio of Ph2P(O)H and NEt the conversion was 75% (Table 2/Entry 2). Using 1.4 equivalents of the P-reagent, the con version dropped to 50% (Table 2/Entry 3). However, when the quantity of NEt3 was in creased to two equivalents, a higher conversion of 90% was attained (Table 2/Entry 4 Triphenylphosphine oxide (1) was obtained in 65 and 85% yields from the better experi ments (Table 2/Entries 2 and 4). One can see that in the P-C coupling reaction under dis cussion, CuBr is a more efficient catalyst than CuI. Then, CuCl was applied as the catalyst precursor. The tendencies observed were sim ilar experienced with CuBr, but the conversions were somewhat lower. Applyin Ph2P(O)H and the base in a one equivalent quantity, the conversion was 71% as compare to 75% (Table 2/Entry 5 vs. entry 2). Increasing the quantity of the P-reagent to 1.4 equiv alents, the conversion was 47% against the value of 50% (  In the next stage, different Cu + precursors were tested in the model reaction selected. Applying 20% of CuBr as the catalyst at 165 °C for 3 h at a 1:1 ratio of Ph2P(O)H and NEt3, the conversion was 75% (Table 2/Entry 2). Using 1.4 equivalents of the P-reagent, the conversion dropped to 50% (Table 2/Entry 3). However, when the quantity of NEt3 was increased to two equivalents, a higher conversion of 90% was attained (Table 2/Entry 4). Triphenylphosphine oxide (1) was obtained in 65 and 85% yields from the better experiments (Table 2/Entries 2 and 4). One can see that in the P-C coupling reaction under discussion, CuBr is a more efficient catalyst than CuI. Then, CuCl was applied as the catalyst precursor. The tendencies observed were similar experienced with CuBr, but the conversions were somewhat lower. Applying Ph2P(O)H and the base in a one equivalent quantity, the conversion was 71% as compared to 75% (Table 2/Entry 5 vs. entry 2). Increasing the quantity of the P-reagent to 1.4 equivalents, the conversion was 47% against the value of 50% ( Then, CuCl was applied as the catalyst precursor. The tendencies observed were similar experienced with CuBr, but the conversions were somewhat lower. Applying Ph 2 P(O)H and the base in a one equivalent quantity, the conversion was 71% as compared to 75% (Table 2/Entry 5 vs. entry 2). Increasing the quantity of the P-reagent to 1.4 equivalents, the conversion was 47% against the value of 50% (Table 2/Entry 6 vs. entry 3). When NEt 3 was used in an excess (two equivalents), a conversion of 84% was observed that was somewhat lower than the value of 90% obtained with CuBr ( In conclusion, the higher conversions around 89% belonging to CuBr and CuCl catalyst precursors were obtained using two equivalents of NEt 3 . One may see that CuBr was found the most efficient catalyst precursor in the series investigated. On the other hand, it may be observed from the experimental data that probably not the P-Cu(I)-P (A) complex is the active species, but rather the P-Cu(I)-N (B) or the N-Cu(I)-N (C) complex. The mixed ligation may be more realistic, as in this case, the reacting P moiety is also included. This problem will be discussed in the theoretical part, see Section 2.4.2.) Bis(4-methylphenyl)phosphine oxide and bis(3,5-dimethylphenyl)phosphine oxide were also tested in the P-C coupling reactions applying Cu salt catalyst precursors (20%) at 165 • C in EtOH as the solvent. Applying CuCl in reaction with the 4-MePh derivative, it was better to use 2 equivalents of NEt 3 as compared to the case with only 1 equivalent of the amine, as marked by the conversions of 80% and 68%, respectively (Table 3/Entries 2 and 1). In the presence of CuBr, the conversion was better (83%) ( Table 3/Entry 3). Table 3. Extensions of the Cu-catalyzed P-C coupling reaction to substituted diarylphosphine oxides.
In conclusion, the higher conversions around 89% belonging to CuBr and CuCl cata-lyst precursors were obtained using two equivalents of NEt3. One may see that CuBr was found the most efficient catalyst precursor in the series investigated. On the other hand, it may be observed from the experimental data that probably not the P---Cu(I)---P (A) complex is the active species, but rather the P---Cu(I)---N (B) or the N---Cu(I)---N (C) complex. The mixed ligation may be more realistic, as in this case, the reacting P moiety is also included. This problem will be discussed in the theoretical part, see Section 2.4.2.) Bis(4-methylphenyl)phosphine oxide and bis(3,5-dimethylphenyl)phosphine oxide were also tested in the P-C coupling reactions applying Cu salt catalyst precursors (20%) at 165 °C in EtOH as the solvent. Applying CuCl in reaction with the 4-MePh derivative, it was better to use 2 equivalents of NEt3 as compared to the case with only 1 equivalent of the amine, as marked by the conversions of 80% and 68%, respectively (Table 3/Entries 2 and 1). In the presence of CuBr, the conversion was better (83%) ( Table 3/Entry 3). Applying bis(3,5-dimethylphenyl)phosphine oxide as the P-reagent and ligand, somewhat higher (77, 87 and 90%) conversions were detected under the conditions applied above. (Compare entries 1 and 4, entries 2 and 5, as well as entries 3 and 6 of Table  3). Although appearance of the methyl group in position 4 of the phenyl ring slightly decreases the reactivity of the secondary phosphine oxide in the P-C coupling reaction under discussion, the steric hindrance due to the methyl groups may increase the activity of the catalyst formed, as in this case, bis-ligation is preferred [10]. After purification, diarylphenylphosphine oxides 2 and 3 were obtained in yields of 78% and 84%, respectively.
It can be seen that the methyl substitution in the phenyl ring is somewhat disadvantageous in the Hirao reaction. In order to prove this directly, competitive P-C couplings were carried out applying a 1:1 mixture of Ph2P  (Table 4/Entries 1 and 2), meaning that the secondary phosphine oxide is more reactive with phenyl groups than with 4-MePh and 3,5-diMePh substituents. The methyl group in position 4 results in larger electron density on the P atom increasing its complexation ability; at the same time, this Applying bis(3,5-dimethylphenyl)phosphine oxide as the P-reagent and ligand, somewhat higher (77, 87 and 90%) conversions were detected under the conditions applied above. (Compare entries 1 and 4, entries 2 and 5, as well as entries 3 and 6 of Table 3). Although appearance of the methyl group in position 4 of the phenyl ring slightly decreases the reactivity of the secondary phosphine oxide in the P-C coupling reaction under discussion, the steric hindrance due to the methyl groups may increase the activity of the catalyst formed, as in this case, bis-ligation is preferred [10]. After purification, diaryl-phenylphosphine oxides 2 and 3 were obtained in yields of 78% and 84%, respectively.
It can be seen that the methyl substitution in the phenyl ring is somewhat disadvantageous in the Hirao reaction. In order to prove this directly, competitive P-C couplings were carried out applying a 1:1 mixture of Ph 2 P(O)H and Ar 2 P(O)H in reaction with iodobenzene. The interrupted reactions revealed a 20:12 and a 23: (Table 4/Entries 1 and 2), meaning that the secondary phosphine oxide is more reactive with phenyl groups than with 4-MePh and 3,5-diMePh substituents. The methyl group in position 4 results in larger electron density on the P atom increasing its complexation ability; at the same time, this substituent also results in a decrease in the acidity. In overall, the reactivity decreases. It was found earlier that both electron-donating and electron-withdrawing substituents decrease the reactivity of the bromoarene in P-C coupling reactions [7].

Theoretical Calculations
The computation study on the mechanism and on the energetics was carried out by the DFT method including the implicit solvent model [M06-2X/6-31G(d,p)//PCM(THF)]. The coupling of Ph 2 P(O)H and halobenzenes in the presence of Cu + catalyst served as the model reaction in our calculations. The sketch for the Cu + -catalyzed process is shown in Figure 1. In the first approach, both P-and N-ligation should be assumed, as they are competitive ligands to Cu + . substituent also results in a decrease in the acidity. In overall, the reactivity decreases. It was found earlier that both electron-donating and electron-withdrawing substituents decrease the reactivity of the bromoarene in P-C coupling reactions [7].

Entry
Ar a Based on 31 P NMR.

Theoretical Calculations
The computation study on the mechanism and on the energetics was carried out by the DFT method including the implicit solvent model [M06-2X/6-31G(d,p)//PCM(THF)]. The coupling of Ph2P(O)H and halobenzenes in the presence of Cu + catalyst served as the model reaction in our calculations. The sketch for the Cu + -catalyzed process is shown in Figure 1. In the first approach, both P-and N-ligation should be assumed, as they are competitive ligands to Cu + . From thermodynamic point of view, the overall reaction is exothermic for the two cases involving Br or I as the halogen substituent ( Table 5). The coupling with PhI is more exothermic due to the higher stability of the I − in solution.

Theoretical Calculations
The computation study on the mechanism and on the energetics was carried out by the DFT method including the implicit solvent model [M06-2X/6-31G(d,p)//PCM(THF)]. The coupling of Ph2P(O)H and halobenzenes in the presence of Cu + catalyst served as the model reaction in our calculations. The sketch for the Cu + -catalyzed process is shown in Figure 1. In the first approach, both P-and N-ligation should be assumed, as they are competitive ligands to Cu + . From thermodynamic point of view, the overall reaction is exothermic for the two cases involving Br or I as the halogen substituent ( Table 5). The coupling with PhI is more exothermic due to the higher stability of the I − in solution. From thermodynamic point of view, the overall reaction is exothermic for the two cases involving Br or I as the halogen substituent ( Table 5). The coupling with PhI is more exothermic due to the higher stability of the I − in solution. The reaction unifies three main processes, such as the complexation, oxidative addition of the PhX reactant and finally the reductive elimination from the central metal ion (Figure 1). The catalyst is regenerated in the final stage of the reaction.

Complexation
The complexation process is rather complicated, as Cu + may be ligated with both the tautomeric form of the reagent (Ph 2 POH, 1a) and the trialkylamine that is present as base. There is a multiple possibility for the formation of "Cu + P 4 ", "Cu + N 4 " and the mixed complexes as well. At first, examining only the "homogeneous" complexation, a series of Pand N-ligands were considered up to four ligations. For P-ligation, the complex formation is beneficial in all steps up to the fourth ligation. However, the step-by-step enthalpy values are somewhat decreasing in the order of ligation(s) marked by numbers 1, 2, 3, 4. This is in contrast to the analogous complexation with Pd(0), where due to steric hindrance, the fourth ligation is already unfavorable. It means that despite the steric hindrance, the most preferred form for Cu + is the tetra-coordinated complex. Even triphenylphosphine may be involved in tetracoordination as shown in Figure 2. In case of N-ligation, the sterically less hindered NMe 3 may participate in tetraligation, but the sterically more requiring NEt 3 and N i Pr 3 may be involved in only triple-and bisligation, respectively. The computed values are summarized in Table 6 and visually displayed in Figure 2. According to the computed data, the N-ligation is stronger in the first two steps (1 and 2), but at higher coordinations (such as 3 and 4), the P-ligation overcomes N-ligation. Table 6. Stepwise and accumulated complexation enthalpies (∆H; kJ mol −1 ), Gibbs free energies (∆G; kJ mol −1 ) for the Cu + ion by P-and N-ligands listed in the first column assuming homogeneous complexation. L (Figure 1). The catalyst is regenerated in the final stage of the reaction.

Complexation
The complexation process is rather complicated, as Cu + may be ligated with both the tautomeric form of the reagent (Ph2POH, 1a) and the trialkylamine that is present as base. There is a multiple possibility for the formation of "Cu + P4", "Cu + N4" and the mixed complexes as well. At first, examining only the "homogeneous" complexation, a series of Pand N-ligands were considered up to four ligations. For P-ligation, the complex formation is beneficial in all steps up to the fourth ligation. However, the step-by-step enthalpy values are somewhat decreasing in the order of ligation(s) marked by numbers 1, 2, 3, 4. This is in contrast to the analogous complexation with Pd(0), where due to steric hindrance, the fourth ligation is already unfavorable. It means that despite the steric hindrance, the most preferred form for Cu + is the tetra-coordinated complex. Even triphenylphosphine may be involved in tetracoordination as shown in Figure 2. In case of N-ligation, the sterically less hindered NMe3 may participate in tetraligation, but the sterically more requiring NEt3 and N i Pr3 may be involved in only triple-and bisligation, respectively. The computed values are summarized in Table 6 and visually displayed in Figure 2. According to the computed data, the N-ligation is stronger in the first two steps (1 and 2), but at higher coordinations (such as 3 and 4), the P-ligation overcomes N-ligation.  Extending the study to "heterogeneous" complexation, where NEt3 and Ph2P(O)H are present at the same time and compete with each other; overall, 14 species may be deduced. The map of the possible complexations is presented in Figure 3 together with the stepwise enthalpies computed. Figure 4 summarizes the situation showing that in case of  Extending the study to "heterogeneous" complexation, where NEt 3 and Ph 2 P(O)H are present at the same time and compete with each other; overall, 14 species may be deduced. The map of the possible complexations is presented in Figure 3 together with the stepwise enthalpies computed. Figure 4 summarizes the situation showing that in case of higher ligations, the complexation with P-ligands is more beneficial than that with N-ligands. Extending the study to "heterogeneous" complexation, where NEt3 and Ph2P(O)H are present at the same time and compete with each other; overall, 14 species may be deduced. The map of the possible complexations is presented in Figure 3 together with the stepwise enthalpies computed. Figure 4 summarizes the situation showing that in case of higher ligations, the complexation with P-ligands is more beneficial than that with N-ligands.

Assuming Ph2POH as the Ligand to Cu(I)
Regarding the reaction of Ph2P(O)H with PhX (X = Br or I), in the first approach, the mechanism was modelled assuming the excess of Ph2POH as the ligand to Cu + ion. The bis-coordinated Cu(I) complex was expected to be the most reactive species. In the first step, the most stable "Cu(I)P4" gets decomposed to precatalyst P---Cu(I)---P (4) that is then involved in a series of reaction sequences. The first step is the deprotonation by NEt3 followed by rearrangement to complex [HOPh2P---Cu + ----OPPh2] 4′ that is followed by the interaction of species 4′ with PhX to afford complex 5. Then, the C-X bond of species 5 is Regarding the reaction of Ph 2 P(O)H with PhX (X = Br or I), in the first approach, the mechanism was modelled assuming the excess of Ph 2 POH as the ligand to Cu + ion. The bis-coordinated Cu(I) complex was expected to be the most reactive species. In the first step, the most stable "Cu(I)P 4 " gets decomposed to precatalyst P-Cu(I)-P (4) that is then involved in a series of reaction sequences. The first step is the deprotonation by NEt 3 followed by rearrangement to complex [HOPh 2 P-Cu + --OPPh 2 ] 4 that is followed by the interaction of species 4 with PhX to afford complex 5. Then, the C-X bond of species 5 is cleaved to afford intermediate 6 via TS5,6. In this state (6), the oxidation number of Cu is formally increased to 3+; therefore, this copper cation may be considered as a strong oxidizing agent. The endothermic oxidation of the Cu + ion to Cu 3+ is covered by the beneficial formation and coordination of the halide anion (X − ). The next step involves the formation of the C-P bond via four membered TS6,7, which leads to the loose complex of the final product Ph 3 P (7). In this step, the Cu 3+ is reduced back to Cu + , meanwhile the P(III) is oxidized to P(V). Finally, the Ph 3 PO product (1) leaves the Cu + complex that takes up another P-ligand and a newer aromatic reagent for the next cycle ( Figure 5).

The Mechanism of the Cu(I)-Catalyzed Reaction of Ph2P(O)H with Halogenobenzenes
2.4.1. Assuming Ph2POH as the Ligand to Cu(I) Regarding the reaction of Ph2P(O)H with PhX (X = Br or I), in the first approach, the mechanism was modelled assuming the excess of Ph2POH as the ligand to Cu + ion. The bis-coordinated Cu(I) complex was expected to be the most reactive species. In the first step, the most stable "Cu(I)P4" gets decomposed to precatalyst P---Cu(I)---P (4) that is then involved in a series of reaction sequences. The first step is the deprotonation by NEt3 followed by rearrangement to complex [HOPh2P---Cu + ----OPPh2] 4′ that is followed by the interaction of species 4′ with PhX to afford complex 5. Then, the C-X bond of species 5 is cleaved to afford intermediate 6 via TS5,6. In this state (6), the oxidation number of Cu is formally increased to 3+; therefore, this copper cation may be considered as a strong oxidizing agent. The endothermic oxidation of the Cu + ion to Cu 3+ is covered by the beneficial formation and coordination of the halide anion (X − ). The next step involves the formation of the C-P bond via four membered TS6,7, which leads to the loose complex of the final product Ph3P (7). In this step, the Cu 3+ is reduced back to Cu + , meanwhile the P(III) is oxidized to P(V). Finally, the Ph3PO product (1) leaves the Cu + complex that takes up another P-ligand and a newer aromatic reagent for the next cycle ( Figure 5). The energy diagram ( Figure 6) for the above transformation (Route I) is shown for the P-C couplings of Ph2P(O)H with PhI (green line) and PhBr (red line). It can be seen that the energetics for the two instances go parallelly. However, in the last step, in the reductive elimination, the enthalpy level of the final complexes 7 is rather different: for the X = I case, it is −126.7 kJ mol −1 , while for the X = Br instance, the value is −320.6 kJ mol −1 . The energy diagram ( Figure 6) for the above transformation (Route I) is shown for the P-C couplings of Ph 2 P(O)H with PhI (green line) and PhBr (red line). It can be seen that the energetics for the two instances go parallelly. However, in the last step, in the reductive elimination, the enthalpy level of the final complexes 7 is rather different: for the X = I case, it is −126.7 kJ mol −1 , while for the X = Br instance, the value is −320.6 kJ mol −1 . Regeneration of the catalyst is more feasible from the iodo containing complex (7, X = I), as this goes with enthalpy gain, as shown in the last step of Figure 6. The sharp difference between the Br − and I − may be explained by the stronger and irreversible binding of Br − to the central Cu + ion, as compared to I − . This may be an explanation for the experience that PhBr cannot be coupled with Ph 2 P(O)H in the presence of Cu + -catalyst applied in a quantity of 10-20%.
Enthalpy, Gibbs free energy and entropy values belonging to the species involved in Figure 6 are listed in Table 7.  as this goes with enthalpy gain, as shown in the last step of Figure 6. The sharp difference between the Br − and I − may be explained by the stronger and irreversible binding of Br − to the central Cu + ion, as compared to I − . This may be an explanation for the experience that PhBr cannot be coupled with Ph2P(O)H in the presence of Cu + -catalyst applied in a quantity of 10-20%. Enthalpy, Gibbs free energy and entropy values belonging to the species involved in Figure 6 are listed in Table 7.

Assuming Mixed P, N-Ligation and N,N-Ligation of Cu(I)
We also studied the first reaction step (Route I, oxidative addition of the PhBr to the Cu + ion) assuming the P-Cu(I)-N (8) and the N-Cu(I)-N (9) complexes as active catalysts (Figure 7). The P-Cu(I)-P (4) species may undergo exchange of one of its P-ligands to TEA that is present in the mixture leading to "mixed" P-Cu(I)-N complex 8. Another replacement may afford N-Cu(I)-N complex 9. The relative enthalpy levels of the three binary Cu(I) complexes (4, 8 and 9) are shown on the left side of Figure 8, representing that the N-ligation brings the highest stability.
We also studied the first reaction step (Route I, oxidative addition of the PhBr to the Cu + ion) assuming the P---Cu(I)---N (8) and the N---Cu(I)---N (9) complexes as active catalysts (Figure 7). The P---Cu(I)---P (4) species may undergo exchange of one of its P-ligands to TEA that is present in the mixture leading to "mixed" P---Cu(I)---N complex 8. Another replacement may afford N---Cu(I)---N complex 9. The relative enthalpy levels of the three binary Cu(I) complexes (4, 8 and 9) are shown on the left side of Figure 8, representing that the N-ligation brings the highest stability.  Enthalpy, Gibbs free energy and entropy values belonging to the additional species shown in Figure 8 are listed in Table 8. Enthalpy, Gibbs free energy and entropy values belonging to the additional species shown in Figure 8 are listed in Table 8. Table 8. Computed reaction enthalpy (∆H), Gibbs free energy (∆G) in kJ mol −1 and entropy values (∆S) in J mol −1 K −1 for Route II-III in respect to Figure 8. The values for the diphosphate complex, can be found in Table 7.  (8 ). In the case of P-ligation, the deprotonation by TEA is beneficial, consequently, the deprotonated and then rearranged complexes (4 and 8 ) should be considered as the active forms. 8 then undergoes complexation with PhBr and the species (10) so obtained will be the subject of a subsequent oxidative addition to furnish intermediate 11 via TS10,11. The next step is the reductive elimination from 11 to afford the loose complex of Ph 3 P(O) (12) via TS11,12. The energetics of the transformations under discussion are summarized in Figure 8. One can see that the oxidative addition step involving species 10 goes with a significantly lower activation enthalpy (21.8 kJ mol −1 ), as compared to that belonging to species 5 of the original route (51.4 kJ mol −1 ).
As it was mentioned above, the mixed P-Cu(I)-N complex (8)  It may be concluded that the involvement of the P-Cu(I)-N complex (8) is the most favorable catalyst in Hirao reaction under discussion. Preparative experiments (see Section 2.1) confirmed that the use of two equivalents of the >P(O)H reagent (for the catalyst precursor) is harmful, while the application of NEt 3 in an excess is beneficial. This phenomenon may be explained assuming that the complexation of Cu(I) with the tautomeric form of >P(O)H (>POH) may proceed until tetraligation that prevents the catalytic process. It is also possible that the complexation of Cu(I) with >POH is irreversible, or in this case, the ligand exchange is very slow kinetically, while the complexation with NEt 3 is reversible.
Comparing the three analogous reaction mechanisms (Route I-III), one can conclude that the P-containing complexes exhibit significantly lower activation enthalpy in the oxidative addition step, than the bis N-complex. Both the P-Cu(I)-P and P-Cu(I)-N complexes may be relevant, as the activation barriers do not differ significantly. It is noteworthy that the thermodynamic stability of the Cu(III)PN and Cu(III)P 2 complexes at the intermediate state is much lower than that of the Cu(III)N 2 species. Moreover, the Cu(III)N 2 complex needs to undergo a ligand exchange (and then a deprotonation and isomeration) to have the phosphine reactant involved. In addition, using PhBr as the starting material, regeneration of the CuL 2 complex is not possible due to the high enthalpy requirement. Experiments confirmed that PhI is the suitable reactant in the Cu(I)-catalyzed P-C couplings.
As it may be observed in the mechanism (shown in Figure 8), the thermodynamic stability of the central copper ion with different oxidation states (I and III) is significantly influenced by the surrounding ligands. The relative enthalpy for the oxidation process of Cu(I) to Cu(III) strongly decreases with the increase of the number of the P-ligands (0→1→2) in the complex (see Figure 9). Considering the oxidation process Cu(I)→Cu(III), the stepwise exchange of the N-ligands (NEt 3 ) by a P-ligand goes with decreasing enthalpy differences of 1571.6 kJ mol −1 → 1410.2 kJ mol −1 → 1361.2 kJ mol −1 . This unambiguously shows that a P-ligand may bring a higher stability for the Cu(III) oxidation state than the N-ligand. This trend is in contrast with the situation for Cu(I). It means, that the lone electron pair of the P atom may provide a larger electron density for Cu(III) than the N atom. Moreover, this energetic stabilization is not linear, as the first N→P ligand exchange results in a more significant gain (56.6 kJ mol −1 ) as compared to that assumed for the linear correlation (see red dot and the arrow in Figure 9). In other words, the N→P ligand exchange is exothermic for Cu(I), but endothermic for Cu(III).

General Information
The reactions were carried out in a CEM ® Discover Model SP (300 W) (CEM, Microwave Technology Ltd., Buckingham, UK) focused microwave reactor equipped with a stirrer and a pressure controller using 80-100 W irradiation under isothermal conditions. The reaction mixtures were irradiated in sealed borosilicate glass vessels (with a volume of 10 mL) available from the supplier of CEM ® . The reaction temperature was monitored by an external IR sensor. The 31 P, 13 C and 1 H NMR spectra were taken in CDCl3 solution on a Bruker AV-300 spectrometer (Bruker Corp., Billerica, MA, USA) operating at 121.5, 75.5 and 300 MHz, respectively. The 31 P chemical shifts are referred to H3PO4, while the 13 C and 1 H chemical shifts are referred to TMS. The couplings are given in Hz. The exact mass measurements were performed using an Agilent 6545 Q-TOF mass spectrometer (Agilent, Santa Clara, CA, USA) in high resolution, positive electrospray mode.

General Information
The reactions were carried out in a CEM ® Discover Model SP (300 W) (CEM, Microwave Technology Ltd., Buckingham, UK) focused microwave reactor equipped with a stirrer and a pressure controller using 80-100 W irradiation under isothermal conditions. The reaction mixtures were irradiated in sealed borosilicate glass vessels (with a volume of 10 mL) available from the supplier of CEM ® . The reaction temperature was monitored by an external IR sensor.
The 31 P, 13 C and 1 H NMR spectra were taken in CDCl 3 solution on a Bruker AV-300 spectrometer (Bruker Corp., Billerica, MA, USA) operating at 121.5, 75.5 and 300 MHz, respectively. The 31 P chemical shifts are referred to H 3 PO 4 , while the 13 C and 1 H chemical shifts are referred to TMS. The couplings are given in Hz. The exact mass measurements were performed using an Agilent 6545 Q-TOF mass spectrometer (Agilent, Santa Clara, CA, USA) in high resolution, positive electrospray mode. (Table 1/Entry 9, Table 2

/Entries 4 and 8)
To 0.099 mmol of the catalyst (CuI: 0.019 g, CuBr: 0.014 g, CuCl: 0.0098 g) in 1 mL of ethanol were added 0.49 mmol (0.055 mL) of iodobenzene, 0.49 mmol (0.10 g) of diphenylphosphine oxide and 0.99 mmol (0.14 mL) of triethylamine. Then, the resulting mixture was irradiated in a closed vial in the microwave reactor at 165 • C for the times (3 or 4 h) shown in Tables 1 and 2. The reaction mixtures were diluted with 3 mL of EtOH, filtrated and the residue obtained after evaporation was passed through a thin (2-3 cm) layer of silica gel using dichloromethane-methanol 97:3 as the eluent. The crude mixture was analyzed by 31 P NMR spectroscopy, then it was purified by column chromatography (silica gel and ethyl acetate-hexane as the eluent). To 0.087 mmol of the catalyst (CuCl: 0.0086 g, CuBr: 0.012 g) in 1 mL of ethanol were added 0.048 mL (0.43 mmol) of iodobenzene, 0.43 mmol of diarylphosphine oxide [bis(4methylphenyl)phosphine oxide: 0.10 g or bis(3,5-dimethylphenyl)phosphine oxide: 0.11 g] and 0.87 mmol (0.12 mL) of triethylamine. Then, the resulting mixture was irradiated in a closed vial in the microwave reactor at 165 • C for 4 h. The reaction mixtures were diluted with 3 mL of EtOH, filtrated and the residue obtained after evaporation was passed through a thin (2-3 cm) layer of silica gel using dichloromethane-methanol 97:3 as the eluent. The crude product was analyzed by 31 P NMR spectroscopy, then it was purified by column chromatography (silica gel and ethyl acetate-hexane as the eluent). For the results see Table 3.

General Procedure for the Competitive Coupling Reaction of Iodobenzene with Diarylphosphine Oxides
To 0.050 mmol (0.0049 g) of copper(I) chloride in 1 mL of ethanol were added 0.50 mmol (0.056 mL) of iodobenzene, 0.25 mmol (0.051 g) of diphenylphosphine oxide, 0.25 mmol of diarlyphosphine oxide (bis(4-methylphenyl)phosphine oxide: 0.058 g or bis(3,5-dimethylphenyl) phosphine oxide: 0.065 g) and 0.55 mmol (0.077 mL) of triethylamine. Then, the mixture was irradiated in a closed vial in the microwave reactor at 165 • C for 1.5 h. The reaction mixtures were diluted and filtrated and the residue obtained after concentration was passed through a thin (2-3 cm) layer of silica gel using dichloromethane-methanol 97:3 as the eluent. The crude product was analyzed by 31 P NMR spectroscopy. For the results see Table 4.

Conclusions
The so far less spread and studied Cu(I)-catalyzed Hirao P-C coupling reaction of iodobenzene and diarylphosphine oxides may be best carried out using 20% of CuBr catalyst precursor and two equivalents of triethylamine in ethanol at 165 • C under MW irradiation. The theoretical calculations following a careful study on the P-and N-ligation of Cu(I) proved that the >P(OH)-Cu(I)-NEt 3 "mixed" complex may be the primary catalyst and in the rate determining oxidative addition step, Cu(I) is converted to Cu(III). The "homogeneous" complex P(III)-Cu(I)-P(III) may also be involved in a lesser extent, but the other homogeneous species, Et 3 N-Cu(I)-NEt 3 could be excluded on the basis of the energetics. The calculations also suggested that bromobenzene is not a suitable starting material in the P-C couplings investigated. This is the first case that the Cu(I)-catalyzed Hirao reaction was optimized and the mechanism of the P-C coupling was explored.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/catal11080933/s1, 31 P, 1 H, and 13 C NMR spectra of products, energetics and geometrical data belonging to theoretical calculations.

Conflicts of Interest:
The authors declare no conflict of interest.