Effect of the leaving group and the allylic structure on the kinetics and thermodynamics of the reaction of allylic carboxylates with palladium(0) complexes

The reaction of allylic carboxylates (allyl-OZ, OZ: acetate, chloroacetate, trifluoroacetate, substituted benzoates, carbonate) with Pd 0 complexes ligated by monodentate (PPh 3 ) or bidentate (dppb, dppf) ligands is a reversible multistep reaction, which eventually gives in DMF a cationic ( η 3 -allyl)Pd II (P P) + complex with ZO − as the counter anion (free ions). The formation of an intermediate neutral complex ( η 2 -allyl-OZ)Pd 0 (P P) where the Pd 0 is ligated to the C=C bond of the allylic carboxylate (complexation step) has been evidenced kinetically in the case of moderate OZ leaving groups (acetate, benzoates) for monodentate and bidentate phosphine ligands. The overall equilibrium constants and the rate constants of the complexation and oxidative addition-ionization steps (when not too fast) have been determined in DMF. With very good leaving groups (carbonate, trifluoroacetate), the oxidative addition-ionization step is faster than the complexation step whereas the oxidative addition-ionization step is the slowest step for less good leaving groups (acetate, benzoate). The forward rate constant of the equilibrium in which the active Pd 0 (PPh 3 ) 2 is formed from Pd 0 (dba)(PPh 3 ) 2 has been determined.


Introduction
3][4] The reaction proceeds in two successive steps: reversible complexation followed by a reversible oxidative addition (also called ionization step) (Eq.1).The intermediate Pd 0 complex ligated by the C=C bond of the allyl acetate has been kinetically evidenced when the Pd 0 is ligated by bidentate bisphosphine ligands (dppb or dppf). 3) AcO _ Pd 0 OAc Pd 0 (P P) + OAc + Pd + P P P P The reversibility of the reaction of a cyclic allylic carbonate has also been established with PPh 3 as well as an epimerization at the allylic position. 5Consequently, in a palladium-catalyzed nucleophilic allylic substitution, the acetate or carbonate ions whose concentration increases as the catalytic reaction proceeds, may compete with poor or stabilized nucleophiles in the nucleophilic attack on cationic (η 3 -allyl)palladium(II) complexes, leading thus to scrambling in the allylic substrates. 5,6This shows that acetate or carbonate ions are not only simple leaving groups as generally postulated, but that they may play an active role in the catalytic process. 6e report therein the effect of the leaving group and the structure of the allylic group on the kinetics and thermodynamics of the reaction of allylic carboxylates with palladium(0) complexes.

Scheme 1
Reaction of an allyl carboxylate with Pd 0 (dba)(P P) in DMF (PP represents either 2PPh 3 or one bidentate P,P ligand) With a large excess of the allylic carboxylate or with a very reactive allylic carboxylate, the reaction (2) may be irreversible.The apparent rate constant k 1 app = K 0 k 1 /C 0 of the overall complexation step [3] (Scheme 1) was then determined from UV kinetic data.The rate of formation of the cationic complex (η 3 -allyl)Pd(P P) + was monitored by conductivity measurements.The rate constant, k 2 (Scheme 1) was determined when the ionization step was rate determining. [3]netics and thermodynamics of the reaction of allyl carboxylates with Pd 0 complexes as a function of the leaving group With PPh 3 as the ligand (Table 1, entries 1-12), one observes that the reaction of allyl carboxylates CH 2 =CH-CH 2 -OZ (Eq 2) is irreversible when considering very good OZ leaving groups such as carbonate and trifluoroacetate (Table 1, entries 1-4).The reversibility of the reaction could not be evidenced, even in the presence of a large excess of dba or PPh 3 or at low temperatures.The rate constants of the chemical steps (k 1 app and k 2 , Scheme 1) were too fast to be determined at 20 °C.This was achieved at lower temperatures (Table 1, entries 2,3) for the rate constant of the complexation step, k 1 app .For the -OCOCF 3 leaving group, the kinetic curve of the formation of the cationic complex was strictly exponential (no S-shaped) with a rate of formation equal to the rate of disappearance of Pd 0 (dba)(PPh 3 ) 2 .This establishes that the rate of the oxidative addition-ionization step from the intermediate complex (η 2 -CH 2 =CH-CH 2 -OCOCF 3 )Pd 0 (P P) is faster than its rate of formation, which is then rate determining:

see last paragraph for the detailed mechanistic investigation of this reaction).
The reaction ( 2) is an equilibrium for less good leaving groups such as chloromethylacetate, benzoates and acetate (Table 1, entries 5-12).As expected, the determination of the equilibrium constants shows that the better the leaving group, the higher the equilibrium constant.In the benzoates series (Table 1, entries 6-11), the substitution of the phenyl group by an electron withdrawing group, which exalts the leaving group properties, favors the formation of the cationic complex (η 3 -allyl)Pd(P P) + .All these data are consistent with the effect of the leaving group.A good leaving group will favor the two forward reactions: the complexation step because the C=C double bond becomes less electron rich, and the oxidative addition step in which the leaving group is released.A good leaving group is also a poor nucleophile for the backward reaction of the last step (rate constant k -2 ).Consequently as expected, the better the leaving group, the higher the equilibrium constant and the higher the concentration of the cationic complex (η 3 -allyl)Pd(P P) + .In the benzoate series (CH 2 =CH-CH 2 -OBz), the rate constants k 1 app and k 2 were determined at 10 °C.The kinetic curves for the formation of the cationic complexes were all S-shaped.This is an evidence for the formation of the intermediate complex (η 2 -CH 2 =CH-CH 2 -OBz)Pd 0 (PPh 3 ) 2 , with the overall complexation step slightly faster than the oxidative addition step (k . The fact that the rate constants k 1 app and k 2 increase with the increasing ability of the leaving groups to leave is thus consistent (  1, entries 17,18), the effect of the leaving group is the same as that observed for PPh 3 : the better the leaving group, the higher the equilibrium constant (i.e., the higher the concentration of the cationic (η 3 -allyl)Pd(P P) + complex) and the higher k 1 app .The effect of the leaving group on the rate constant of the ionization step k 2 is consistent in the benzoates series ( Kinetics and thermodynamics of the reaction of allylic carboxylates/carbonates with Pd 0 complexes as a function of the structure of the allylic group For a similar leaving group and a similar ligand, either PPh 3 (Table 2, entries 1,2) or dppb (Table 2, entries 3,4), the equilibrium constant decreases, as well as k 1 app and k 2 , when a phenyl group is substituted on the allylic structure.
In the carbonate series (Table 2, entries 5,6), the equilibrium constant considerably decreases when the steric hindrance of the allylic carbonate increases.The steric hindrance disfavors both the complexation and ionization steps.The ionization step is faster than the complexation (Table 2, entry 7), which is consistent with the good leaving group property of the carbonate (such a situation was also encountered with the leaving group -OCOCF 3 , Table 1, entry 3).
Reaction of the allyl trifluoroacetate with the Pd 0 generated from Pd 0 (dba) 2 and 2 equiv.PPh 3 in DMF The reaction order in dba is −1 (Figure 1A).The reaction order in CH 2 =CH-CH 2 -OCOCF 3 was determined by plotting the observed rate constant k obs (s -1 ) of the formation of the cationic complex versus CH 2 =CH-CH 2 -OCOCF 3 concentration (Figure 1B).A reaction order of +1 was found at low CH 2 =CH-CH 2 -OCOCF 3 concentrations but at higher concentrations, a saturation effect was observed with a reaction order of zero (Figure 1B).This means that at high CH 2 =CH-CH 2 -OCOCF 3 concentrations, the reaction rate is no longer determined by the complexation of Pd 0 (PPh 3 ) 2 by the allyl trifluoroacetate but by the step, which delivers the reactive Pd 0 (PPh 3 ) 2 (k 0 in Scheme 2).The kinetic law for the formation of the intermediate (η 2 -CH 2 =CH-CH 2 -OCOCF 3 )Pd 0 (PPh 3 ) 2 is then given in Eq 3 (allyl stands for CH 2 =CH-CH 2 -OCOCF 3 ). (4) At low CH 2 =CH-CH 2 -OCOCF 3 and high dba concentrations: k -0 [dba] > k 1 [allyl] and 1/k obs = [dba]/k 1 K 0 [allyl].k 1 K 0 is then determined from the slope of the regression line of Fig 1A. [9] The general equation ( 3) is shown in reciprocal form in Eq 4. The plot of 1/k obs versus the reciprocal of CH 2 =CH-CH 2 -OCOCF 3 concentration is indeed found to be linear with a positive intercept (Fig 1C), which justifies the saturating effect observed at high CH 2 =CH-CH 2 -OCOCF 3 concentrations and supports the mechanism given in Scheme 2. k 0 is then determined from the intercept. 100 = 0.17 s −1 in DMF at -10 °C It is worthwhile to note that this is the first determination of the forward rate constant k 0 of the equilibrium between Pd 0 (dba)(PPh 3 ) 2 and Pd 0 (PPh 3 ) 2 .This determination was possible because we have, for the first time, a very reactive reagent for which, at high concentrations (> 0.02M), the following inequality is fulfilled: [dba].k 0 becomes then the rate determining step of the overall reaction and can be measured experimentally.
In conclusion, the reaction of allylic carboxylates or carbonates with Pd 0 complexes (first step of the Tsuji-Trost reaction) is reversible and involves the formation of an intermediate complex (η 2 -allyl-OZ)Pd 0 (P P) (complexation step) whatever the phosphine ligand, monodentate or bidentate, examined here.This step is followed by the formation of a cationic (η 3 -allyl)Pd II (P P) + complex with ZO − as the counter anion (ionization step).The better the leaving group OZ, the higher the concentration of the cationic complex.For good leaving groups (carbonate, trifluoroacetate) the ionization step is faster than the complexation step whereas the ionization step is rate determining for poorer leaving groups (acetate, benzoate).
The reaction of cyclic allylic carbonates proceeds with isomerization at the allylic position. 5This result is not limited to the allylic carbonates since we recently observed that the reaction of a cyclic allylic benzoate also proceeds with isomerization at the allylic position. 11This definitively demonstrates that the role of the leaving group in Tsuji-Trost reactions is certainly more complex than usually considered and may play a significant kinetic role.

Experimental Section
General Procedures.UV spectra were recorded on a DU 7400 Beckman spectrophotometer in a thermostated 1 mm length cell.Conductivity measurements were performed with a Tacussel CD6NG Conductivity Meter.The value of the cell constant was K = 0.9 cm -1 .General procedure for the kinetic investigations by UV spectroscopy All experiments were performed in DMF under Argon on solutions of Pd 0 (dba) 2 (1 mM) and PPh 3 (2 mM).[4][5] General procedure for the kinetic investigations by conductivity measurements All experiments were performed in DMF under Argon on solutions of Pd 0 (dba) 2 (1 mM) and PPh 3 (2 mM) (except for experiments reported in Figure 1 where the Pd 0 (dba) 2 concentration was 2 mM and PPh 3 concentration 4 mM).][4][5]

Table 1 .
Effect of the leaving group OZ on the reaction of allyl carboxylates CH 2 =CH-CH 2 -OZ with Pd 0 complexes generated in situ from Pd 0 (dba) 2 (C 0 = 1 mM) and 2 equiv.PPh 3 or 1 equiv.dppfordppb, in DMF.Comparative equilibrium constants K (Eq 2) and rate constants k 1 app and −1 s −1 is the maximum rate constant that can be determined by UV spectroscopy under our experimental conditions (t 1/2 = 2s for C 0 = 1 mM and [allyl-OZ] = 5 mM).c non determined because the reaction was too fast.dForCH 2 =CH-CH 2 -OCOCF 3 concentrations smaller than 0.02 M (see Fig1B).For a given bidentate ligand, either dppf (Table1, entries 13-16) or dppp (Table a For a given ligand, the leaving groups are classified in order of decreasing ability to leave when going down the table.b Fast reaction: 100 M

Table 2 .
Effect of the allylic structure on the reaction of allyl carboxylates/carbonates with Pd 0 complexes generated in situ from Pd 0 (dba) 2 (C 0 = 1 mM) and 2 equiv.PPh 3 or 1 equiv.dppb, in DMF.Comparative equilibrium constants K (Eq 2) and rate constants k 1 app and k 2 (Scheme 1) a Non determined because the reaction was too fast.