|Home | About | Journals | Submit | Contact Us | Français|
This communication describes detailed investigations of the mechanism of the Pd-catalyzed C-H chlorination and acetoxylation of 2-ortho-tolylpyridine. Under the conditions examined, both reactions proceed via rate limiting cyclopalladation. However, substrate and catalyst order as well as Hammett data indicate that the intimate mechanism of cyclopalladation differs significantly between PdCl2-catalyzed chlorination and Pd(OAc)2-catalyzed acetoxylation.
Palladium-catalyzed ligand-directed C-H bond functionalization has become a valuable synthetic method for the selective oxidation of organic molecules.1 Over the past 5 years, numerous Pd-catalyzed reactions have been developed for the directed oxygenation,2 halogenation,3 amination,4 sulfonylation,5 and arylation1b-e of both sp2 and sp3 C-H bonds. Furthermore, these transformations have been applied to structurally diverse organic scaffolds, including amino acid derivatives2c and drug substrates.6
While significant progress has been made in the development of new reactions, detailed mechanistic studies in this area have received considerably less attention.7,8 An improved mechanistic understanding could facilitate (i) the development of new catalysts with improved catalytic activity and substrate scope as well as (ii) the rational implementation of strategies for controlling the chemo-, diastereo-, enantio- and site-selectivity of C-H functionalization reactions. This communication describes an investigation of the mechanism of pyridine-directed C-H bond chlorination with N-chlorosuccinimide (NCS). We report on the optimization of the precatalyst, elucidation of the turnover limiting step, and mechanistic comparison to related Pd-catalyzed C-H acetoxylation reactions.
Pd-catalyzed C-H chlorination has been proposed to proceed by the general catalytic cycle outlined in Scheme 1.3,8c,9,10 This cycle begins with ligand directed C-H activation (i), which is followed by two electron oxidation of the resulting palladacycle to a monomeric PdIV species (or a closely related PdIII~PdIII dimer) (ii).8c Finally, C-Cl bond-forming reductive elimination (iii) regenerates the catalyst and releases the functionalized product. Previous studies have demonstrated that electrophilic chlorinating reagents like N-chlorosuccinimide (NCS)10 and PhICl28c,10 can promote the stoichiometric two electron oxidation of cyclometalated Pd(II) complexes, demonstrating the viability of step (ii) of the proposed catalytic cycle. However, detailed investigations of the turnover limiting step, the kinetic isotope effect, and the electronic requirements of C-H chlorination have thus far not been explored.
Our mechanistic investigation focused on the Pd-catalyzed functionalization of 2-ortho-tolylpyridine (1) with NCS and PhI(OAc)2 to form 2 and 3, respectively (Table 1). Substrate 1 possesses several desirable features. First, it undergoes selective mono-functionalization. Second, it participates cleanly in both C-H chlorination and C-H acetoxylation reactions, thus allowing direct comparison of these two transformations. Finally, the pyridine ring is readily modified, which facilitates analysis of electronic effects in these systems.11 Our studies began with conditions analogous to those in the literature: 5 mol % of Pd(OAc)2 and 1.2 equiv of NCS in CH3CN with  = 0.12 M.3c However, at this concentration the reactions did not remain homogeneous, which led to inconsistent kinetics; furthermore, when  was lowered, competing formation of acetoxylated product 3 was observed,12 which complicated kinetic analysis.
Based on these preliminary studies, we surveyed a variety of alternative Pd sources (Table S2) and identified PdCl2 as an optimal catalyst for the chlorination of 1 in MeCN. Further optimization revealed that 5 mol % of PdCl2 is required to achieve full conversion and that the highest yield (80%) is obtained at concentrations between 0.048 and 0.024 M. Importantly, these conditions also worked well for the Pd(OAc)2-catalyzed ortho-acetoxylation of 1, providing 3 in 77% yield.
With optimal conditions for the chlorination and acetoxylation of 1 in hand,13 we first examined the intermolecular kinetic isotope effect (KIE) for the two reactions. The Pd-catalyzed functionalizations of 1 and 1-d1 were monitored by GC, and the initial rates method was used to determine the rate at each [oxidant]. As shown in Table 1, a large 1° isotope effect was observed in both systems, with kH/kD = 4.4 ± 0.2 for chlorination and kH/kD = 4.3 ± 0.5 for acetoxylation.14
We next established the kinetic order in each reaction component, starting with the oxidant. As shown in Figure 1, for both NCS and PhI(OAc)2 the initial rate was independent of [oxidant] over a wide range of concentrations (12-144 mM or 0.5-3.0 equiv oxidant relative to substrate).
The kinetic order in palladium was next determined for each transformation by varying the catalyst loading from 2.5 to 10 mol % ([Pd] = 0.6-4.8 mM) under otherwise identical conditions. As shown in Figure 2, chlorination showed a 1st order dependence on [Pd] over this catalytically relevant concentration range. In contrast, for the C-H acetoxylation reaction, a plot of initial rate versus [Pd] was clearly not linear. A weighted non-linear least squares fit of the data to the equation: f(x) = a[Pd]n provided an order (n) of 1.5 ± 0.2 (Figure 2).
Finally, the order in substrate 1 was examined, using 0.25-2.5 equiv of 1 relative to oxidant ( = 6-120 mM). Again, the chlorination and acetoxylation reactions showed different results (Figure 3). For chlorination, a plot of initial rate versus  showed that the rate was independent of . In contrast, the acetoxylation reactions showed an inverse 1st order dependence on .
To gain insight into the electronic requirements of these reactions, we next probed the initial rate of C-H functionalization with a series of electronically different 2-ortho-tolylpyridines. As shown in Figure 4, Hammett plots for both C-H chlorination and C-H acetoxylation showed a modest correlation with the σ values of the Y and Z substituents. Very different ρ values were obtained for the two reactions, with ρ = -0.43 for chlorination and ρ = +0.89 for acetoxylation.15
The data presented here offer valuable insights into the mechanistic similarities and differences between the Pd-catalyzed chlorination and acetoxylation of substrate 1. The large 1° intermolecular KIE coupled with the zero order dependence on [oxidant] provide strong evidence that both transformations proceed via turnover limiting cyclopalladation. This is in interesting contrast to the C-H arylation of 3-methyl-2-phenylpyridinewith [Ar2I]BF4, which was proposed to involve turnover limiting oxidation of a cyclometalated Pd(II) dimer.7e
While the rate determining step appears to be the same in both of the current systems, the different kinetic orders in [Pd] and in  as well as the different Hammett ρ values are consistent with different mechanisms for cyclopalladation in the PdCl2 versus Pd(OAc)2-catalyzed reactions. Significant literature precedent has shown that PdX2 (X = OAc or Cl) reacts rapidly and quantitatively with excess amine or pyridine derivatives (L) to form monomeric complexes of general structure Pd(X)2(L)2.16 For example, Pd(OAc)2(ba)2 (ba = benzylamine), has been directly observed in the Pd(OAc)2-mediated cyclometalation of benzylamine in MeCN.17 As such, we propose that the catalyst resting state during both C-H functionalizations is most likely Pd(X)2(1)2 (X = Cl, 4; X = OAc, 7) (Schemes (Schemes22 and and33).18
In the chlorination reaction, the observed zero order dependence on  suggests that cyclometalation at Pd(Cl)2(1)2 (4) proceeds by either: (a) direct C-H activation via a 5-coordinate transition state such as 519 or (b) pre-equilibrium chloride dissociation followed by C-H activation at cationic complex 6.20 Paths a and b are both consistent with the observed kinetic orders of 1 in [Pd] and 0 in .18 Furthermore, both mechanisms have been proposed for related cyclometalation reactions in the literature.19,20 We tend to favor path b, as it offers a better explanation for the Hammett ρ value of -0.43. The latter can be rationalized based on increased lability of Cl- (at complex 4) and MeCN (at complex 6) with more electron releasing pyridine ligands. This would lead to an increase in both Keq and k1, thereby affording faster reactions with electron rich pyridines.
For the acetoxylation reaction, the observed inverse first order dependence on  implicates pre-equilibrium dissociation of 1 from Pd(OAc)2(1)2 prior to C-H activation. As shown, in Scheme 3, this could generate monomeric species Pd(OAc)2(1)(MeCN) (8) (path c) or an acetate-bridged dimer such as Pd2(OAc)4(1)3 (9) (path d), and cyclometalation could then occur at either of these intermediates. Path c is expected to show a 1st order dependence on [Pd], while path d should be 2nd order in [Pd] (Scheme 3). We propose that these (or other closely related) competing 1st and 2nd order mechanisms are likely responsible for the observed 1.5 order dependence on [Pd] in this system.21 The Hammett ρ value of +0.89 is fully consistent with this mechanistic proposal, as electron withdrawing substituents on the pyridine ligand should both increase Keq and also render complexes 8 and 9 more more reactive towards electrophilic C-H activation (thereby increasing both k1 and k2).7b,19b,c Notably, mechanisms similar to both c17 and d18 have been proposed for the stoichiometric cyclometalation of benzylamine at Pd(OAc)2 in MeCN.17
There are several important ramifications of these studies. First, it is clear that the ligand environment at Pd during C-H activation is significantly different in these two transformations. If this result proves general, it has potential implications for diastereoselectivity in the C-H functionalization of chiral substrates upon changing the catalyst/oxidant combination. In addition, the structures of the key intermediates (as well as the possibility of competing mechanisms) should inform the selection of chiral ligands for asymmetric C-H functionalization reactions. Finally, the development of more highly active C-H chlorination and acetoxylation catalysts will require accelerating the cyclometalation step of the catalytic cycle. Because most ancillary ligands decrease the rate of directed C-H activation relative to that with simple Pd salts, this is a particularly challenging problem that will likely require the design of novel ligands.
In summary, this communication describes the mechanism of Pd-catalyzed directed C-H chlorination and acetoxylation of 1. Under the conditions examined, both reactions proceed via turnover limiting cyclopalladation. However, kinetic order and Hammett data indicate that the intimate mechanism of C-H activation differs significantly between PdCl2-catalyzed chlorination and Pd(OAc)2-catalyzed acetoxylation. Ongoing work seeks to further explore the proposed mechanisms computationally as well as exploit the current results for the development of new C-H functionalization catalysts.
We thank the NIH NIGMS (GM-073836) for support of this research. KJS also acknowledges Novartis for a graduate fellowship. Finally, we thank Frontier Scientific for a generous gift of 2-methylboronic acid.