The Carbopalladation Mechanism

Despite Martensson et al. [43] experimentally showed that the carbopalladation mechanism can not be operative, in order to have a comprehensive mechanistic understanding of the reaction we decided to investigate this mechanism together with the deprotonation mechanism including their cationic and anionic alternatives (see below). 

The theoretical investigation of the copper-free Sonogashira reaction with pheny-lacetylene as a model substrate (R = H) through a carbopalladation mechanism afforded the reaction profile shown in Fig. 5.5. 

Overall, the reaction is exergonic by 21.5 kcal mol but the carbopalladation mechanism has a very high energy barrier (40.4 kcal mol ), which makes this 

With the carbopalladation reaction pathway established for phenylacetylene (R = H) and for the sake of completeness, the effect of the alkyne R substituent on the overall carbopalladation mechanism was next examined. With this purpose, the Gibbs energy profiles for the Sonogashira reaction with several 4-substituted pheny-lacetylenes (R = CF3, OMe, NMe2) through a carbopalladation mechanism were computed (Table 5.1). 

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Addition of CO to C=C and C=C bonds provides an alternative approach to lactones distinct from that of C—X and C—M carbonylation [6, 24]. In particular, hydrocarbonylation involves the formation of new C—H and C—C bonds (Scheme 2.12). Pd-catalyzed transformations of this type proceed through either hydropalladative or carbopalladative pathways [6]. In the carbopalladative mechanism, a Pd alkoxide undergoes carbonylation, yielding an acylpalladium species. Subsequent insertion into the C=C or C=C bond generates the desired lactone. Hydropalladation, on the other hand, is favored under reducing or acidic conditions and occurs via Pd hydride addition to the unsaturation, followed by CO insertion, and reductive elimination. 

Fig. 5.5 Gibbs energy profile in DCM AGdcm, kcal mol ) at 298 K for the carbopalladation mechanism with R = H, and Base = pyrrolidine...

Fig. 5.6 Optimized structures for the transition states involved in the carbopalladation mechanism with phenylacetylene (R = H). Distances are shown in A...

With the carbopalladation mechanism ruled out as operative mechanism, the copper-free Sonogashira reaction through a deprotonation mechanism was next investigated. As commented in the introduction, for this mechanism two different alternatives have been proposed, namely the cationic and the anionic mechanisms (Fig. 5.3) [43]. This two mechanistic alternatives only differ in the order in which the steps in the deprotonation mechanism occur. 

The theoretical calculations presented so far demonstrate that the carbopalladation mechanism is not operating under the reaction conditions. Furthermore, calculations also show that the other three investigated mechanisms (i.e. cationic, anionic and ionic mechanisms) may have competitive rates. Thus, a change on the reaction conditions (i.e. solvent, ligands, substrates, base, etc.) might favor one or another mechanism. 

To probe the reaction mechanism of the silane-mediated reaction, EtjSiD was substituted for PMHS in the cyclization of 1,6-enyne 34a.5 The mono-deuterated reductive cyclization product 34b was obtained as a single diastereomer. This result is consistent with entry of palladium into the catalytic cycle as the hydride derived from its reaction with acetic acid. Alkyne hydrometallation provides intermediate A-7, which upon cw-carbopalladation gives rise to cyclic intermediate B-6. Delivery of deuterium to the palladium center provides C-2, which upon reductive elimination provides the mono-deuterated product 34b, along with palladium(O) to close the catalytic cycle. The relative stereochemistry of 34b was not determined but was inferred on the basis of the aforementioned mechanism (Scheme 24). 

Another variant of the Heck reaction which is important in heterocyclic chemistry utilizes five membered heterocycles as olefin equivalent (2.2.)7 It is not clear whether the process, coined as heteroaryl Heck reaction follows the Heck mechanism (i. e. carbopalladation of the aromatic ring followed by //-elimination) or goes via a different route (e.g. electrophilic substitution by the palladium complex or oxidative addition into the C-H bond). Irrespective of these mechanistic uncertainties the reaction is of great synthetic value and is frequently used in the preparation of complex policyclic structures. 

A mechanistic rationale for the Pd-catalyzed addition of a C-H bond at nitriles to allenes is outlined in Scheme 3. The oxidative insertion of Pd(0) into the C-H bond of nitrile 1 produces the Pd(II) hydride species 16 (or alternatively a tautomeric structure E E2C=C=N PdH Ln may be more suitable, where E = H, alkyl, aryl and/or EWG). Carbopalladation of the allene 2 would afford the alkenylpalladium complex 17 (carbopalladation mechanism), which would undergo reductive coupling to give the addition product 3 and regenerates Pd(0) species. As an alternative mechanism, it may be considered that the hydropalladation of allenes with the Pd(II) intermediate 16 gives the jr-allylpalladium complex 18 which undergoes reductive coupling to afford the adduct 3 and a Pd(0) species (hydropalladation mechanism). 

For the Heck reaction as discussed in Section III.2.1 the final position of the olefi-nic double bond of the products must not necessarily be the same as in the starting materials (for example Schemes 8, 9, and 10 of Section III.2.1) [1], The selectivity is often driven by stereochemical requirements, because the /1-hydrogen elimination step which forms the double bond proceeds exclusively in a syn manner (if a trans /3-hydrogen is eliminated, one should suspect major deviations from the general mechanism of the Heck reaction, for example electrophilic substitution instead of carbopalladation). An impressive example of a double bond migration is depicted in Scheme 1 - instead of olefins the coupling reaction of iodobenzene 1 with the olefmic alcohol 2 results in the isomeric aldehydes 3 and 4 as final products [2], Reactions of this type have emerged as valuable tools for the synthesis of carbonyl compounds and also as crucial steps in domino processes. 

Step 5 of the mechanism shown in Figure 16.35 (part II) is new. It consists of the cw-selec-tive addition of the aryl-Pd complex to the C=C double bond of the acrylic acid methyl ester, i.e., a carbopalladation of this double bond. A related reaction, the cw-selective car-bocupratlon of C=C triple bonds, was mentioned in connection with Figure 16.17. The regioselectivity of the carbopalladation is such that the organic moiety is bonded to the methylene carbon and Pd to the methyne carbon of the reacting C=C double bond. The addition product is an alkyl-Pd(II) complex. 

Oxidative carbonylation of alkenes is a unique reaction of Pd(II). Three types of oxidative carbonylation to give -substituted acid derivatives 130, a, -unsaturated esters 132 and succinate derivatives 134 are known, which can be understood by the following mechanism. Palladation of alkenes with PdX2, followed by CO insertion, generates the acylpalladium intermediate 129 whose reductive elimination affords -substituted carboxylic acid derivatives 130 (path a). Reaction in alcohol in the presence of a base starts by the formation of the alkoxycarbonylpalladium 128. Carbopalladation of alkene with 128 generates 131. Then y3-H elimination of the intermediate 131 yields the a-unsaturated ester 132 (path b). Further CO insertion to 131 gives the acylpalladium intermediate 133 and its alcoholysis yields the succinate derivative 134 (path c). Formation of the jS-alkoxy ester 130 (X-OR) is regarded as nucleophilic substitution of Pd-X in 131 with alcohols. 

The reaction is explained by the following mechanism. At first, Cul activates 1-alkynes 1 by forming the Cu acetylides 6, which undergo transmetallation with arylpalladium halides to form the alkynylarylpalladium species 7, and reductive elimination to give 2 is the final step. However, the coupling proceeds even in the absence of Cul under certain conditions, and it may be possible to form the alkynylarylpalladium species 7 directly from 1-alkynes. As another less likely possibility, carbopalladation of a triple bond with Ar-Pd-X (or insertion of the triple bond to Ar-Pd-X) generates the alkenylpalladium 8 which undergoes dehydropal-ladation to afford disubstituted alkynes 2. In this mechanism, Cul plays no role. The mechanism of -H elimination of alkenylpalladium to form alkynes is not clearly known. 

Ring expansion occurs by the reaction of allenylclobutanols with halides to cyclopentanones [7], hitermolecular reaction of the allenylcyclobutanol 44 with iodobenzene afforded the cyclopentanone 45. Larock and Reddy explained the reaction by the following mechanism. The carbopalladation of the allene with Ph-Pd-I generates the jr-allylpalladium 46, and the concerted rearrangement and ring expansion as shown by 47 provide 48, which isomerizes to 45 [8]. 

In this section, Pd(0)-catalyzed reactions of allenes with nucleophiles are treated, which are clearly different mechanistically from the reactions explained in the above. Attack of nucleophiles may occur at C-1, C-2, and C-3 carbons of the allenes 63. Among them, attack at C-3 to give 64 is predominant. Most importantly, reactions of allenes with pronucleophiles start by the oxidative addition of pronucleophiles to Pd(0) to generate H-Pd-Nu 65. The formation of 64 by hydro-carbonation can be explained in two ways in the case where Nu-H is the carbon pronucleophile. As one possibility, hydropalladation of one of the two double bonds occurs to afford the terminal palladium intermediate 66, which is stabilized by the formation of 7r-allyl complex 67, and reductive elimination provides the C-3 adduct 68. Another possibility is carbopalladation to generate 69, and subsequent reductive elimination provides 68. Of these two possibilities, the hydropalladation mechanism is preferable. 

Yet another important development in the area of Pd-catalyzed carbonylation is the development of acylpalladation and related carbonyl-Pd bond addition reactions. Acylpal-ladation may be defined as a process of acyl-Pd bond addition to alkenes and alkynes. Clearly, it is a kind of carbopalladation reaction. For practical reasons, however, it is discussed in Part VI together with other carbonylation reactions mentioned above. Tsuji and Hosaka " reported in 1965 what appears to be the first example of the perfectly alternating alkene-CO copolymerization (Scheme 8). Independently, Brewis and Hughes reported also in 1965 a Pd-catalyzed cyclic carbonylation of dienes with CO and methanol (Scheme 9). Although the exact mechanism of the initiation is unclear, these reactions... 

Stereochemistry. There are ample experimental indications that both hydropalladation (pattern 5) and carbopalladation (pattern 8) as well as their microscopic reversals (patterns 15 and 18) are, at least in the great majority of cases, strict syn addition processes, as predicted by the concerted mechanism shown in Scheme 8. In the hydropalladation and carobpalladation reactions of alkynes, the stereochemical course of the reactions is readily seen and unmistakable. However, clear-cut and explicit demonstration of the... 

Various metal-metal bonded compounds containing relatively electronegative metals, such as Si, Ge, Sn, B, Al, and Zn, can undergo Pd-catalyzed metallometallation, which mostly involves yn-addition to alkynes. One plausible mechanistic scheme involves (i) oxidative addition of metal-metal bonded compounds to Pd, (ii) metallopalladation (pattern 6) leading to yn-addition of metal-Pd bonds, and (iii) reductive elimination (Scheme 12). As such, the overall mechanism resembles that of Pd-catalyzed hydrogenation or hydrosilation, and the critical metallopalladation step must be mechanistically closely related to those of hydropalladation and carbopalladation. These reactions are discussed in detail in Sect. Vn.5. 

The observed general predominance of cis addition products following the carbopalladation step (Schemes la and 2) and the formation of cyclic derivatives (Scheme lb) appear to argue in favor of a mechanism involving a syn addition of the organic residue and the palladium moiety to the carbon-carbon triple bond. The appearance of final products as trans derivatives is more likely to indicate the intermediacy of cis -adducts capable of isomerization to the tran -adducts (Scheme 3) rather than the existence of a direct trans addition paralleling the cis addition pathway. 

This is illustrated in the mechanism of the Mizoroki-Heck reaction depicted in Scheme 1.22. Indeed, three main factors contribute to slow down the fast oxidative addition of Phi (i) the anion AcO delivered by the precursor Pd(OAc)2, which stabilizes Pd L2 as the less reactive Pd°L2(OAc) (ii) the base (NEts) which indirectly stabilizes Pd L2(OAc) by preventing its decomposition by protons to the more reactive bent Pd L2 (iii) the alhene by complexation of Pd°L2(OAc) to form the nonreactive ( -CH2=CHR)Pd°L2(OAc). On the other hand, the slow carbopalladation is accelerated by the base and by the acetate ions which generate ArPd(OAc)L2, which in turn is more reactive than the postulated ArPdIL2. The base, the alkene and the acetate ions play, then, the same dual role in Mizoroki-Heck reactions deceleration of the oxidative addition and acceleration of the slow carbopalladation step. Whenever the oxidative addition is fast (e.g. with aryl iodides or activated aryl bromides), this dual effect favours the efficiency of the catalytic reaction by bringing the rate of the oxidative addition closer to the rate of the carbopalladation [Im, 34]. 

Regioselectivity is one of the major problems of Mizoroki-Heck reactions. It is supposed to be affected by the type of mechanism ionic versus neutral, when the palladium is ligated by bidentate P P ligands. The ligand dppp has been taken as a model for the investigation of the regioselectivity. Cabri and Candiani [Ig] have reported that a mixture of branched and linear products is formed in Pd°(P P)-catalysed Mizoroki-Heck reactions performed from electron-rich alkenes and aryl halides (Scheme 1.26a) or aryl ttiflates in the presence of halide ions (Scheme 1.26b). This was rationalized by the so-called neutral mechanism (Scheme 1.27). The neutral complex ArPdX(P P) is formed in the oxidative addition of Pd°(pAp) yj Qj. Q aj.yj triflates in the presence of halides. The carbopalladation... 

A unique example of direct olefination of a cyclopropane was also disclosed by the Yu lab [21]. An electron-deficient arylamide was employed as directing group, as the previously employed oxazoline or hydroxamic acid was unreactive in the alkenylation. The proposed mechanism for the reaction involves an amide-directed C-H insertion of the Pd(II) catalyst into the cyclopropane methylene C-H bond of 9, followed by olefin carbopalladation and p-hydride elimination to provide intermediate 10 (Scheme 3a). Pd(0) is re-oxidized back to Pd(II) by Ag(I)/Cu(II), and a tandem 1,4-addition between the amide moiety of 10 and the acrylate provides the corresponding y-lactam 11 as the sole isolated product, fii the presence of an... 

All the key intermediates were detected by ESI-FTICRMS over time, such as those ions of m/z 707.1,891.2 and 1150.3 (Figure 4.2). After these intermediate ions were further characterized by sustained off-resonance irradiation collision-induced dissociation (SORI-CID), one mechanism was proposed as shown in Scheme 4.3. The mechanism involving the carbopalladation with 2-(2,3-allenyl)malonate yielding the 7t-allyl palladium intermediate (Scheme 4.3) was confirmed. 

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