Proton abstraction mechanism

Independent of the thiol protecting groups used in the synthesis of cysteine peptides, the facile racemization of the Cys residue has been recognized as a serious problem since the early days of peptide chemistry (see Section 1.2.1.2 and Vol. E22b, Section 7.4).It is well established that N,S-protected cysteine active esters are unusually prone to racemization via a C -proton-abstraction mechanism in the presence of excess amines (Scheme More... 

The proton-abstraction mechanism is the pathway only in very special cases such as the rapid racemization of derivatives of phenylglycine (Scheme 3). Racemization through the proton-abstraction mechanism can be prevented by employing suitable reaction conditions, in particular by controlling the use of tertiary amine.f " ... 

Garcia-Cuadrado D, Braga AAC, Maseras F, Echavarren AM (2006) Proton abstraction mechanism for the palladium-catalyzed intramolecular arylation. J Am Chem Soc 128 1066-1067... 

Ozdemir I, Demir S, (Jetinkaya B, Gourlaouen C, Maseras F, Bruneau C, Dixneuf PH (2008) Direct arylation of arene C-H bonds by cooperative action of NHCarbene-Ruthenium(II) catalyst and carbonate via proton abstraction mechanism. J Am Chem Soc 130 1156-1157... 

Over the years there have been a number of mechanistic proposals for substrate oxidation by TMADH. An early proposal considered a carbanion mechanism in which an active site base deprotonates a substrate methyl group to form a substrate carbanion [69] reduction of the flavin was then achieved by the formation of a carbanion-flavin N5 adduct, with subsequent formation of the product imine and dihydroflavin. A number of active site residues were identified as potential bases in such a reaction mechanism. Directed mutagenesis and stopped-flow kinetic studies, however, have been used to systematically eliminate the participation of these residues in a carbanion-type mechanism [76-79], thus indicating that a proton abstraction mechanism initiated by an active site residue does not occur in TMADH. Early proposals also invoked the trimethylammonium cation as the reactive species in the enzyme-substrate complex, owing to the high (9.81) of free... 

The same coenzyme binding pattern and no structural changes in the protein component were detectable for the mutant enzymes of transketolase from Saccha-romyces cerevisiae and their complexes with coenzyme analogs studied by X-ray crystallography (Konig et ah, 1994 Wikner et ah, 1994). Summarizing, it can be ruled out that the differences in the H/D exchange rate constants of transketolase from Saccharomyces cerevisiae are a result of a different solvent accessibility of a base involved in the proton abstraction mechanism of ThDP. 

One of the decomposition products if I and II is ferrocene. This ds viewed as further evidence that these Cp U-R complexes decompose by the intramolecular proton abstraction mechanism as seen in the "monomer organoactinide (27, 36). The mass spectrum of I reveals that a cyclopentadienyl ring is lost first (presumably from Cp U) in preference to cleavage of the U-C a bond. 

Both MDI and TDI, being aromatic diisocyanates, yield urethane polymers that tend to yellow on prolonged exposure to sunlight, presumably due to oxidation of some terminal aromatic amine (derived from these isocyanates). MDI also possesses a methylene group that is susceptible to oxidation via a proton abstraction mechanism involving autoxidation of the aromatic urethane groups to a quinoneimide structure as proposed by Schollenberger et al. (24. 25). 

Arylation reactions with the bidentate phosphines most likely proceed by the intermoiecuiar proton-abstraction mechanism, which is supported by DFT calculations as shown in the transformation of 41 into 42 (Scheme 11.12) [39]. Although the addition of pivalic acid has a beneficial effect in many cases, the fact that the... 

Recently, o-alkynyl biaryls have been shown to undergo intramolecular 5-exo-dig hydroarylation by a mechanism that proceeds by a C—H bond activation assisted by the alkynyl substituent [41]. This reaction also proceeds with a palladium complex bearing a dibentate phosphine (l,l -bis(diisopropylphosphinoferrocene)) and shows a sigruficant kinetic isotope effect (ku/ko = 3.5 for the intramolecular process), which is consistent with a mechanism involving a proton-abstraction mechanism. 

The cross-dehydrogenative coupling of N-protected acetanilides such as 112 with arenes proceeds with Pd(II) and Cu(II) via paUadacycles 113 (Scheme 11.38) [147]. Presumably, paUadacycles 113 react with the arenes by a proton-abstraction mechanism via transition state 114 to form Pd(II) complexes 115, which evolve by reductive elimination to yield the coupled products 116. A palladacycle was also involved in the related reaction of acetanilides with boronic acids catalyzed by Pd(ll) and Cu(ll) [148]. 

Anilides react in a general way as arenes in the presence of Pd(OAc)2/DMSO catalyst and TFA in an atmosphere of O2 to give products of ortho-arylation [149]. In this reaction, arenes with electron-withdrawing substituents, such as fluoroben-zene derivatives, gave only poor conversions, which suggests that this reaction does not proceed via a proton-abstraction mechanism. 

Geminal products are formed by proton abstraction mechanism or by a heterolytic P-Cl bond cleavage process. 

Although complex 1 presented an important agostic distortion, the oxidative addition from this species is disfavoured (Scheme 1, pathway a). The introduction of HCO3 in the system results in the coordination of the carbonate to the ruthenium and the formation of adduct 4 which evolves to product 5. The transformation from 3 to 5 is exothermic by 13.7 kcai moi making the proton abstraction mechanism more plausible (Scheme 1, pathway b). 

The coordination of the Pd complex to the reactant via C—Br oxidative addition of the substrate gives intermediate 15. The substitution of Br by an intramolecular base, HCOj , leads to species 16. The energy barrier for the C—H activation is as low as 23.5 kcal/mol, consistent with the experimental temperature of 100-135°C, and occurs via a 6-membered transition state. The authors named this process as proton abstraction mechanism analogous to the acetate-assisted C—H bond activation (AMLA), although in this process bicarbonate instead of acetate is bonded to the metal (see Fig. 25.21). 

One year later, Echavarren and Maseras [33] reported new variants on the proton abstraction mechanism described earlier. In this case, special attention was paid to the substituents on the... 

From a theoretical point of view, the key issue has been the basic nature of the metalation step, where the R groups moves from a R -H bond to a M-R bond. C-H activation is very common in organic chemistry as it allows the formation of functionalized hydrocarbons. Different mechanisms had been proposed for this metalation step, including electrophilic aromatic substitution, a-bond metathesis, oxidative addition/reductiveelimination and Heck-like insertion. Theoretical studies have facilitated narrowing the mechanistic possibilities to two main options oxidative addition/reductive elimination and proton abstraction by a base. In the oxidative addition/reductive elimination process the metal is inserted in the C-H bond with formal increase in the oxidation state of the metal, and the hydride leaves the metal coordination sphere of the metal afterwards. In the proton abstraction mechanism, the metal does not interact directly with the proton, which is captured by a base, with simultaneous formal creation of a carbanion that binds to the metal center. The mechanism of the reaction will depend on the presence of a base able to abstract the proton and of the existence of an energetically accessible oxidation state for the metal. 

Fig. 11.13 Transition state for Ru-catalyzed proton abstraction mechanism of arylation...

Ruthenium-catalyzed arylation seems to favor the proton abstraction mechanism. We studied the coupling of an aryl group to a phenylpyridine moiety [64]. The first step consists of cleavage of a C- H bond to form a Ru-C bond. The two mechanisms, oxidative addition on the ruthenium or H-abstraction, were evaluated. As for palladium, the oxidation of Ru(II) to Ru(IV) is energetically disfavored with a barrier of 133 kJ/mol. The H-abstraction possesses a much lower barrier, 35 kJ/mol with HCOs" as proton abstractor (Fig. 11.13). The barrier of H-abstraction is sensitive to the nature of the base it is only of 22 kJ/mol with acetate. 

Thus the proton abstraction mechanism seems to be the favored pathway in the metalation step of transition-metal-catalyzed arylations. This may seem surprising because a relatively weak base as carbonate is taking away an arylic proton, which has very low acidity. The presence of the metal is in this case key to stabilize the development of a negative charge in the carbon center, as proved by the structure of the transition states, where the metal-carbon bond is practically already formed. It is worth mentioning that external bases are key in both direct arylation and the Suzuki-Miyaura cross-coupling, but their roles are completely different. 

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