Mechanistic insights on the Pd-catalyzed addition of C–X bonds across alkynes – a combined experimental and computational study

A mechanistic study of the Pd-catalyzed intramolecular addition of carbamoyl chlorides and aryl halides across alkynes is presented.

Herein we present a combined computational and experimental study in an effort to understand the underlying mechanism of these transformations and its implication on reactivity. More specically, we aim to shed light on selectivityand reactivity-controlling factors of ligand and substrate and the implicit requirements on alkyne substituent as well phosphine ligand. We hope these results will aid future substrate and catalyst design to further expand the scope of these atomeconomic and synthetically relevant Pd-catalyzed intramolecular transformations.

Computational methods
DFT calculations were performed using Gaussian 09, Revision D.01. 34 Geometry optimizations and frequency calculations were conducted in the gas-phase at the B3LYP/6-31G(d) level of theory, employing LANL2DZ as an ECP for Pd. All stationary points were veried as either minima or transition states. Additionally, transition states (TSs) were conrmed by following the intrinsic reaction coordinate (IRC) to the corresponding intermediates. Energies were calculated at the M06L/def2-TZVP level of theory, employing the CPCM solvation model to account for toluene as the solvent. 35 All energies were converted to 1 M standard state.

General mechanism
The proposed mechanism of the intramolecular addition of aryl halides and carbamoyl chlorides is shown in Scheme 2. On the basis of our calculations, we propose that initial oxidative addition of either aryl halide 1 or carbamoyl chloride 3 to monophosphine Pd(0) is followed by insertion of the alkyne, i.e. cis-carbopalladation. Direct reductive elimination (for aryl halide substrates 1) or rapid cis / trans isomerization and successive reductive elimination (in the case of carbamoyl chloride substrates 3) then yields the observed methylene oxindole products Z-2 and E-5, respectively.
Origin of the superior reactivity of carbamoyl chlorides over aryl chlorides. Our calculations on the intramolecular addition of C(sp 2 )-X (X ¼ Br, Cl) across alkynes indicate that oxidative addition of aryl halide 1 or 4 is the elementary step with the highest activation barrier (Schemes 2 and 4, le). By contrast, the corresponding intramolecular addition of aryl halides across alkenes proceeds with reductive elimination of the C(sp 3 )-X bond (X ¼ I, Br, Cl) as the rate-determining step. 36,37 In the case of the addition of carbamoyl chlorides across alkynes (see Schemes 2 and 4, right), oxidative addition was found to be the TS with the highest activation barrier when a concerted 3-membered TS geometry was considered.
However, while oxidative additions to aryl halides have been subject to extensive computational and mechanistic studies, [38][39][40][41][42][43][44][45] little is known on the nature of the transition state for reactions with carbamoyl chlorides. The high electrophilicity of these species may imply an ionic/electron transfer or formal nucleophilic substitution reaction. By means of computations it is challenging to unambiguously distinguish between these charged and neutral pathways due to the applied computational approximations. 46,47 We therefore designed a test experiment and performed a competitive Suzuki cross-coupling using substrate 6, possessing both aryl chloride and carbamoyl chloride moieties (Scheme 3). 48 An exclusive activation of carbamoyl chloride over aryl chloride was observed experimentally. 49 However, despite the clear preference for oxidative addition of carbamoyl chloride over aryl chloride, the arguably fast oxidative addition step (i.e. fast compared to oxidative addition to aryl chloride) may still be the rate-determining TS of the reaction. Therefore, a resting state analysis of the reaction of 3a and 4a with catalytic Pd/PA-Ph was performed. 48 Almost instantaneous conversion of carbamoyl chloride 3a with concomitant formation of new phosphine-containing species and free ligand was observed by 31 P NMR. In contrast, aryl chloride 4a only yielded traces of product under the same Scheme 1 Experimental data by Lautens and co-workers: (a) intramolecular addition of aryl halides (1) across alkynes, 16 (b) intramolecular addition of carbamoyl chlorides (3) across alkynes. 15 a Reaction was performed at 110 C using 1,2,2,6,6-pentamethylpiperidine (PMP, 0.25 equiv.) as an additive. 16,33 b Yield was determined by 1 H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.
reaction conditions and only one major P-containing species was observed, which is most likely the result of catalyst decomposition. In addition, two species (6.8 and 6.7 ppm by 31 P NMR) were observed for both substrates and are likely to be cisand trans-Pd(II) intermediates, Va and VIa for substrate 3a as well as IIIa and IVa for substrate 4a, respectively. Furthermore, in the reaction of carbamoyl chloride 3a, a species at 5.2 ppm in the 31 P NMR spectrum was formed, which decreased over time and might be the oxidative addition intermediate VIIa. With this information in hand, oxidative addition of carbamoyl chloride 3a is unlikely to be the elementary step with the highest activation barrier. Instead, the observation of potential oxidative addition intermediate VIIa (species at 5.2 ppm in 31 P NMR) suggests alkyne insertion, i.e. carbopalladation to be the turnover-determining transition state (TDTS). Thus, oxidative addition of carbamoyl chloride 3a is suspected to proceed via a fast, possibly ionic, nucleophilic substitution TS rather than a concerted, 3-membered oxidative addition TS. 50 Based on the experimental results, we assume oxidative addition of 3a to be fast and alkyne insertion to be the TDTS for the addition of carbamoyl chlorides across alkynes. Since catalytic turnover depends on both activation barriers (DG ‡ ) and driving force (i.e. reaction free energy, D r G) of the reaction, the free energy difference between the rate-determining intermediate (TDI) and transition state (TDTS), commonly referred to as the energetic span (dE), 51,52 determines the efficiency and speed of the catalytic cycle. Therefore, in order to assess and compare the reactivities of carbamoyl and aryl chlorides in their addition reactions across alkynes, full reaction pathways and their corresponding energetic spans were calculated (Scheme 4). Table 1 shows the calculated energetic spans for the addition of aryl halides (TDTS ¼ oxidative addition) and carbamoyl chlorides (TDTS ¼ alkyne insertion) across alkynes. Further analysis of calculated Gibbs free energy pathways and energetic spans of substrates 3 and 4 revealed insights on the effects of ligand, halide and alkyne substituent on the reaction outcomethe results of which are discussed in detail in the following sections.
Effect of tether moiety. While the developed synthetic protocol for alkyne carbohalogenation was compatible with ether, alkyl and amine tethers (1, Y ¼ O, CH 2 , NTs), employing amide substrates (4) only yielded trace amounts of methylene oxindole product 5. 15 To address the underlying reasons for the incompatibility of the amide tether, DFT calculations were combined with stoichiometric studies.
Stoichiometric studies of 4a (R ¼ TIPS) employing Pd(PtBu 3 ) 2 showed no conversion at 50 C, but when heated at 100 C for 24 h yielded 16% of E-5a, along with 64% of recovered starting aryl chloride 4a. This result indicates that reaction of 4a to form 5a is possible, at least in a stoichiometric manner. However, the higher reaction temperatures lead to catalyst decomposition and thus prevent a catalytic reaction. 52 The observed decomposition of catalyst may be facilitated by the amide moiety. Hence, possible deactivation/side reaction pathways have been investigated computationally (Fig. 1). More specically, transition states for the oxidative insertion of Pd(PA-Ph) to potentially activated bonds of substrates 3a and 4a were calculated and the corresponding activation barriers compared. In the case of the second generation carbamoyl chloride substrate 3a, all bond activations are of higher barrier than oxidative addition via a concerted, 3-membered TS. Notably, this is despite the fact that experiments indicate an even lower barrier for oxidative addition to the carbamoyl chloride via a rapid, possibly ionic, nucleophilic substitution (vide supra). In contrast, for the rst generation aryl chloride substrate 4a, which did not react under analogous reaction conditions, calculations suggest that an activation of the C-Si bond of the alkyne is competing with oxidative addition to the C-Cl bond. This observation is most likely due to an increase in reactivity of the C-Si bond as a result of the conjugation of the alkyne with the amide.
This activation of the alkyne substituent is not present for all other tether moieties (amine, ether, alkyl), therefore providing a potential explanation for the observed difference in reactivity.
Effect of phosphine ligand. While bulky, electron-rich phosphine ligands such as PtBu 3 and QPhos were well-suited Scheme 4 Calculated Gibbs free energy pathways of first and second generation substrates 3a and 4a possessing an amide tether. Energies (in kcal mol À1 ) were calculated at the CPCM (toluene) M06L/def2-TZVP//B3LYP/6-31G(d)(LANL2DZ) level of theory. Abbreviations: oxidative addition (OA), alkyne insertion (AI), cis / trans isomerization (Isom) and reductive elimination (RE).   for the addition of aryl halides across alkenes 36,37 and alkynes 16 (vide infra), their use in the addition of carbamoyl chlorides across alkynes only led to small amounts of product being formed. This might be due to the change in TDTS. While oxidative addition is the rate-determining TS for the rst generation aryl halide substrate 4, alkyne insertion was considered to be the TDTS for the second generation carbamoyl chloride substrate 3. In the case of aryl halide substrate 4, the bulky PtBu 3 ligand facilitates the reductive elimination of product (Scheme 5), thereby reducing the Gibbs free energy of the reaction (D r G) compared to the corresponding reaction of 4 with the less bulky PA-Ph ligand ( Table 1, entries 1 and 3). In contrast, in the case of carbamoyl chloride 3, the less bulky PA-Ph facilitates the presumed rate-determining alkyne insertion and lowers its activation by approximately 5 kcal mol À1 compared to the corresponding process employing the bulkier PtBu 3 ligand (Scheme 5). This directly causes a signicant decrease in energetic span ( Table 1, entry 4), thus explaining the superior reactivity observed for PA-Ph in comparison to the bulkier PtBu 3 ligand (entry 5).

Silyl effect
Experimentally, only substrates bearing a silyl-substituent on the alkyne were reactive in the chlorocarbamoylation reaction, whereas substrates with a mesityl-substituted alkyne did not cyclize under analogous reaction conditions. Next, we investigated the role of the alkyne substituent computationally. A signicant increase in energetic span for mesityl-substituted substrates 4b and 3b (Table 1, entries 2 and 6, respectively) was observed compared to substrates 4a and 3a bearing a TIPS-substituent (entries 1 and 5, respectively). When comparing the energetic pathways for substrates 3a (R ¼ TIPS) and 3b (R ¼ Mes), an effect of the TIPS-moiety was observed on (i) cis / trans isomerization and (ii) reductive elimination (Scheme 6). More specically, the TIPS-group leads to a signicant destabilization of Pd(II) intermediates VI and V, along with a stabilization of the transition state for cis / trans isomerization, which causes a substantial decrease in the barrier of isomerization and overall results in a atter energetic pathway and thus a smaller energetic span. Steric effects of the silyl group. While for TIPS-substituted Pd(II) intermediates, the trans-intermediate Va is more stable than its corresponding cis-intermediate VIa, the opposite preference is observed for the mesityl-substituted Pd(II) intermediates, i.e. VIb is more stable than Vb. Overall, both Pd(II) intermediates VIa and Va are signicantly destabilized by the TIPS-moiety compared to the corresponding mesitylsubstituted intermediates (VIb and Vb). However, the degree of destabilization is more pronounced for the cis-Pd(II) intermediate VIa. This would be in agreement with an increased steric interaction of the TIPS moiety with the aryl group of the oxindole in VIa compared to Va. In contrast, the mesityl moiety can rotate away (into a side-on conformation), in which there is signicantly less steric interaction, thus rendering the Pdsubstituent the most sterically congesting moiety. Therefore, the preference of VIb over Vb appears to be due to a decreased steric interaction of PdCl(PtBu 3 ) with the aromatic backbone of the oxindole. 48 Electronic effects of the silyl group. In order to investigate the nature of the cis / trans isomerization TS, we analyzed (i) the charge distribution in the Pd(II)-intermediates, VIa and Va, as well as during the isomerization TS and (ii) the change in bond lengths from cis-intermediate VIa via the TS to transintermediate Va (Fig. 2). For this reason, a natural bond order analysis (NBO analysis) 54-57 was performed, which showed that only a minor change in charge separation occurs in the case of TIPS, whereas a signicant buildup of charge separation takes place for R ¼ Mes. More specically, TIPS-substituted intermediates VIa and Va already possess a high degree of charge separation with a positive charge of +0.53 on the silyl substituent and only a minor increase of 4% leads to the isomerization TS (positive charge of +0.55 on the silyl moiety). In contrast, mesityl-substituted intermediates do not exhibit signicant charge separation (+0.03 and +0.08 on mesityl for intermediates VIb and Vb, respectively) and a substantial separation of charges needs to be established (increase of 136%) in order to reach the charge-separated TS (with a positive charge of +0.16 on mesityl). This analysis is in line with calculated Atoms-In-Molecules (AIM) 58 charges, which indicate essentially no change in charge on Si (increase of 0.2%) to reach the isomerization TS, but a strong increase in charge of 77% on the ipso-C of the mesityl-substituent in order to undergo isomerization. 48 These results are congruent with the observed energetic destabilization of TIPS-substituted Pd(II)-intermediates VIa and Va and indicate that the low barrier for cis / trans isomerization for R ¼ TIPS is primarily a result of a destabilization of intermediates rather than a stabilization of the TS. Moreover, charge separation is much larger in the presence of the silyl substituent, suggesting that the TIPS-moiety can better stabilize charge buildup and thus lowers the barrier for the isomerization process.
This result is in agreement with the known effect of silyl groups to be able to stabilize carbocations in a, 59   and Si. 48 This corresponds with the calculated Mayer bond orders, 63,64 which indicate a decrease in bond order of the C]C double bond during the TS for both R ¼ TIPS and R ¼ Mes, although more pronounced for the latter. At the same time, the C-R (R ¼ TIPS or Mes) bond order increases during isomerization (indicating delocalization of charge into the R-substituent). This increase is only minor for the silyl moiety (increase of 8%), but more evident for mesityl (increase of 20%) as expected due to the bigger required changes in order to reach the TS. 48 Overall, the silyl moiety exerts a combination of effects on several intermediates and steps in the chlorocarbamoylation reaction, giving rise to its unique reactivity.

Origins of observed divergence in selectivity
In the reaction of carbamoyl chlorides an exclusive E-selectivity is reached by means of a rapid cis / trans isomerization (see Scheme 1b). However, in the corresponding reaction of aryl halides medium to good levels of Z-selectivity are observed as a result of direct reductive elimination. In the case of mesityl substituted alkynes, a switch in selectivity (i.e. to obtain E-2b) can be reached at elevated reaction temperatures (see Scheme 1a). Additionally, the substrate scope is not limited to TIPSsubstituted alkynes, tolerating other bulky groups, such as aryls for example.
Analysis of the calculated free energy pathways revealed a pronounced effect of the alkyne substituent on the reactivity prole (Scheme 7). Analogous to reactions of the amide-tethered substrates 3 and 4 (Schemes 4-6), a TIPS-substituent favors the cis-Pd(II) intermediate IIIa, but the corresponding transintermediate IV is more stable when possessing a mesityl-substituent (IVb). In addition, the barrier towards isomerization is signicantly lower for R ¼ TIPS compared to R ¼ Mes, i.e. DG ‡ ¼ 5.8 and 13.1 kcal mol À1 for substrates 1a (R ¼ TIPS) and 1b (R ¼ Mes), respectively. Moreover, the stability of the precomplexes PC_1, where the active monophosphine Pd(0) (PtBu 3 ) species coordinates to the alkyne group of substrate 1, is more pronounced when R ¼ TIPS, indicating that the silyl group increases the electrophilic character of the alkyne moiety. This would suggest that the reductive elimination from the vinyl Pd(II) intermediates, III and IV, is reversible for substrates 1b and 1d bearing a mesityl-substituent. In combination with the trans-Pd(II) intermediate IV being more stable than the cis-intermediate III, a reversal of the observed Z-selectivity for R ¼ Mes (at 50 C) can be reached at elevated reaction temperatures (at 100 C). 16,65 Conclusions The mechanisms of alkyne carbohalogenation and chlorocarbamoylation have been investigated by means of DFT calculations and experiments. Catalytic pathways involving oxidative addition, alkyne insertion, cis / trans isomerization and reductive elimination are proposed. Oxidative addition is suggested to be reactivity limiting in the case of addition of aryl halides across alkynes: in the corresponding reaction of carbamoyl chlorides, oxidative addition was however shown to be fast and our data indicated that instead alkyne insertion, i.e. carbopalladation was reactivity limiting. Furthermore, the effects of halide, phosphine ligand and alkyne substituent on reactivity were investigated.
While the bulky PtBu 3 was vital for reactivity in the intramolecular addition of aryl halides across alkynes due to a lowering of the barriers for reductive elimination, the less bulky phosphaadamantane ligand PA-Ph is uniquely suited for the corresponding addition reaction of carbamoyl chlorides. Calculations indicate that this is due to a signicant decrease in the barrier for the reactivity limiting alkyne insertion with the less bulky PA-Ph ligand compared to PtBu 3 . Notably, a pronounced effect of the alkyne substituent on reactivity was unravelled, which accounts for the exceptional reactivity of substrates bearing a TIPS-substituent. More specically, the bulky TIPS-group was shown to cause a signicant destabilization of Pd(II) intermediates VI and V, along with a stabilization of the cis / trans isomerization TS. This overall results in a smaller energetic span and thus signicantly increases catalytic turnover.