Free radical polymerization with catalytic chain transfer: Using NMR to probe the strength of the cobalt–carbon bond in small molecule model reactions

This work examines cobalt–carbon bond formation between the cobalt (II) macrocycle, (tetrakis(p‐methoxyphenyl)porphyrinato)cobalt (II), (TAP)Co, and a variety of radicals derived from vinyl compounds to facilitate a better understanding of the various factors affecting the cobalt–carbon bond strength in catalytic chain transfer polymerization. The reaction of (TAP)Co with the following vinylic molecules was studied: methacrylonitrile, cyclohexene, methyl methacrylate, styrene, methyl acrylate, vinyl acetate, vinyl benzoate, methyl crotonate, cis‐2‐pentenenitrile, and ethyl α‐hydroxymethacrylate. Different concentrations of each vinylic compound were added to (TAP)Co and 2,2′‐azobis(isobutyronitrile) in CDCl₃ at 60 °C. The ratio of Co(III) to Co(II) and the nature of the radical bound to the cobalt macrocycle were determined via nuclear magnetic resonance measurements. Several factors are shown to affect the reaction of the radical and the cobalt (II) species (and hence the strength of the cobalt–carbon bond in the resulting compound). These factors are as follows: the number of pathways by which a radical may be derived from the vinyl compound; the variety of radicals that can be produced from the vinylic molecule; the stability of the radical(s) generated; and the relative propagation rate of the vinyl compound. A discussion on the relevance of this study to the behavior of different monomers in catalytic chain transfer reactions is included. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6171–6189, 2006     

Cob(I)alamin als Katalysator. 1. Mitteilung. Reduktion von gesättigten Nitrilen in wässeriger Lösung

Co(I)alamin as Catalyst. 1. Communication. Reduction of Saturated Nitriles in Aqueous Solution Using cob(I)alamin as homogeneous catalyst in the presence of aqueous acetic acid saturated nitriles 5a – m are reduced to the corresponding aldehydes 6a – m in good yields. A possible reaction mechanism for this reduction is discussed.     

Evidence for the formation of a cis-dichlorovinyl anion upon reduction of cis-1,2-dichlorovinyl(pyridine)cobaloxime

The reduction of cis-1,2-dichlorovinyl(pyridine)cobaloxime, a model complex for the organometallic intermediate proposed in the dechlorination of trichloroethylene by cobalamin, was studied. Two mechanisms were considered for the Co-C bond cleavage following reduction. In the first, the Co-C bond cleaves to produce Co(I) and a chlorovinyl radical, while the second pathway results in the formation of Co(II) and a chlorovinyl anion. Four reducing agents, cobaltocene, decamethylcobaltocene, cob(I)alamin, and chromium(II), were used in the presence of H atom and proton donor species to identify the presence of chlorovinyl radical or chlorovinyl anion intermediates. Mechanistic conclusions were based on comparisons of the final product ratios of cis-dichloroethylene (cDCE) and chloroacetylene, which were found to have a direct relationship to the amount of proton donor available, with increased proton donor leading to increased cDCE production. The results support the intermediacy of a cis-1,2-dichlorovinyl anion.     

Stabilisation of methylene radicals by cob(II)alamin in coenzyme B12 dependent mutases

Coenzyme B12 initiates radical chemistry in two types of enzymatic reactions, the irreversible eliminases (e.g., diol dehydratases) and the reversible mutases (e.g., methylmalonyl-CoA mutase). Whereas eliminases that use radical generators other than coenzyme B12 are known, no alternative coenzyme B12 independent mutases have been detected for substrates in which a methyl group is reversibly converted to a methylene radical. We predict that such mutases do not exist. However, coenzyme B12 independent pathways have been detected that circumvent the need for glutamate, beta-lysine or methylmalonyl-CoA mutases by proceeding via different intermediates. In humans the methylcitrate cycle, which is ostensibly an alternative to the coenzyme B12 dependent methylmalonyl-CoA pathway for propionate oxidation, is not used because it would interfere with the Krebs cycle and thereby compromise the high-energy requirement of the nervous system. In the diol dehydratases the 5'-deoxyadenosyl radical generated by homolysis of the carbon-cobalt bond of coenzyme B12 moves about 10 A away from the cobalt atom in cob(II)alamin. The substrate and product radicals are generated at a similar distance from cob(II)alamin, which acts solely as spectator of the catalysis. In glutamate and methylmalonyl-CoA mutases the 5'-deoxyadenosyl radical remains within 3-4 A of the cobalt atom, with the substrate and product radicals approximately 3 A further away. It is suggested that cob(II)alamin acts as a conductor by stabilising both the 5'-deoxyadenosyl radical and the product-related methylene radicals.     

Thermodynamic trans-Effects of the Nucleotide Base in the B12 Coenzymes

The thermodynamic effects of the nucleotide coordination on the Co-C bond strengths in the B ₁₂ coenzymes were analyzed. Methyl group transfer reactions from methylcob( III )inamides to cob( II )inamides and cob( I )inamides in neutral aqueous solution were used in equilibration experiments to determine the effect fo the intramolecular coordination of the nucleotide function on the Co-C bond dissociation energies of methylcob( III )alamin ( 4 ). In the equilibrium between 4 , cob( I )inamide ( 11 ), cob( I )alamin ( 10 ) and methylcob( III )inamide 6 (Scheme 2), 4 and 11 were found to predominate ( 4 + 11 ? 10 + 6 , equilibrium constant K_I/III≈0.004), while the equilibrium between 4 , cob( II )inamide 9 , cob( II )alamin ( 5 ), and 6 (Scheme 1) proved to be well balanced ( 4 + 9 ? 5 + 6 , equilibrium constant K_II/III=0.60). These equilibrium values indicate the nucleotide coordination to stabilize the Co–C bond in 4 both against homolysis (slight effect) and against nucleophilic heterolysis (considerable effect). They reflect a stabilization of the complete corrins 4 and 5 by the nucleotide coordination, which is also indicated for 4 and 5 by their (nucleotide) basicity. The latter information, where available for other organocobalamins, allows the analysis of the thermodynamicnucleotide trans effect there as well: e.g. in coenzyme B ₁₂ ( 1 ), the nucleotide coordination is found this way to weaken the Co–C bond towards homolysis by ca. 0.7 kcal/mol.     

Diastereoselective synthesis of branched 2-deoxy sugars via radical c-c bond formation reactions

From glycals 1 and 6, 2-deoxy sugars can be synthesized in 40–72% yields. With 1,2-disubstituted alkenes 3 this radical C-C bond formation reaction leads with high stereoselectivity to the isomers 4 and 8.     

Stabilisation of Methylene Radicals by Cob(II)alamin in Coenzyme B12 Dependent Mutases

Coenzyme B₁₂ initiates radical chemistry in two types of enzymatic reactions, the irreversible eliminases (e.g., diol dehydratases) and the reversible mutases (e.g., methylmalonyl‐CoA mutase). Whereas eliminases that use radical generators other than coenzyme B₁₂ are known, no alternative coenzyme B₁₂ independent mutases have been detected for substrates in which a methyl group is reversibly converted to a methylene radical. We predict that such mutases do not exist. However, coenzyme B₁₂ independent pathways have been detected that circumvent the need for glutamate, β‐lysine or methylmalonyl‐CoA mutases by proceeding via different intermediates. In humans the methylcitrate cycle, which is ostensibly an alternative to the coenzyme B₁₂ dependent methylmalonyl‐CoA pathway for propionate oxidation, is not used because it would interfere with the Krebs cycle and thereby compromise the high‐energy requirement of the nervous system. In the diol dehydratases the 5′‐deoxyadenosyl radical generated by homolysis of the carbon–cobalt bond of coenzyme B₁₂ moves about 10 Å away from the cobalt atom in cob(II )alamin. The substrate and product radicals are generated at a similar distance from cob(II )alamin, which acts solely as spectator of the catalysis. In glutamate and methylmalonyl‐CoA mutases the 5′‐deoxyadenosyl radical remains within 3–4 Å of the cobalt atom, with the substrate and product radicals approximately 3 Å further away. It is suggested that cob(II )alamin acts as a conductor by stabilising both the 5′‐deoxyadenosyl radical and the product‐related methylene radicals.     

Theoretical calculations of carbon-oxygen bond dissociation enthalpies of peroxyl radicals formed in the autoxidation of lipids

Theoretical calculations were carried out to provide a framework for understanding the free radical oxidation of unsaturated lipids. The carbon[bond]hydrogen bond dissociation enthalpies (BDEs) of organic model compounds and oxidizable lipids (R[bond]H) and the carbon[bond]oxygen bond dissociation enthalpies of peroxyl radical intermediates (R[bond]OO*) have been calculated. The carbon[bond]hydrogen BDEs correlate with the rate constant for propagation of free radical autoxidation, and the carbon[bond]oxygen BDEs of peroxyl radicals correlate with rate constants for beta-fragmentation of these intermediates. Oxygen addition to intermediate carbon radicals apparently occurs preferentially at centers having the highest spin density. The calculated spin distribution therefore provides guidance about the partitioning of oxygen to delocalized carbon radicals. Where the C[bond]H BDEs are a function of the extent of conjugation in the parent lipid and the stability of the carbon radical derived therefrom, C[bond]OO* BDEs are also affected by hyperconjugation. This gives way to different rates of beta-fragmentation of peroxyl radicals formed from oxygen addition at different sites along the same delocalized radical. We have also studied by both theory and experiment the propensity for benzylic radicals to undergo oxygen addition at their ortho and para carbons which, combined, possess an equivalent unpaired electron spin density as the benzylic position itself. We find that the intermediate peroxyl radicals in these cases have negative C[bond]OO* BDEs and, thus, have rate constants for beta-fragmentation that exceed the diffusion-controlled limit for the reaction of a carbon-centered radical with oxygen.     

Theoretical investigations into the intermediacy of chlorinated vinylcobalamins in the reductive dehalogenation of chlorinated ethylenes

The reductive dehalogenation of perchloroethylene and trichloroethylene by vitamin B(12) produces approximately 95% (Z)-dichloroethylene (DCE) and small amounts of (E)-DCE and 1,1-DCE, which are further reduced to ethylene and ethane. Chloroacetylene and acetylene have been detected as intermediates, but not dichloroacetylene. Organocobalamins (RCbls) have been proposed to be intermediates in this process. Density functional theory based approaches were employed to investigate the properties of chlorinated vinylcobalamins and chlorinated vinyl radicals. They reveal that all vinyl radicals studied have reduction potentials more positive (E degrees >or= -0.49) than that of the Co(II)/Co(I) couple of B(12) (E degrees = -0.61 V), indicating that any (chlorinated) vinyl radicals formed in the reductive dehalogenation process should be reduced to the corresponding anions by cob(I)alamin in competition with their combination with Co(II) to yield the corresponding vinylcobalamins. The computed Co-C homolytic bond dissociation enthalpies (BDEs) of the latter complexes range from 33.4 to 45.8 kcal/mol. The substituent effects on the BDEs are affected by the stabilities of the vinyl radicals as well as steric interactions between (Z)-chloro substituents and the corrin ring. The calculated E degrees values of the cobalamin models were within approximately 200 mV of one another since electron attachment is to a corrin ring pi-orbital, whose energy is relatively unaffected by chloride substitution of the vinyl ligand, and all were >500 mV more negative than that of the Co(II)/Co(I) couple of B(12). Reduction of the base-off forms of vinyl- and chlorovinylcobalamin models also involves the corrin pi* orbital, but reduction of the base-off dichlorovinyl- and trichlorovinylcobalamin models occurs with electron attachment to the sigma(Co)(-)(C*) orbital, yielding calculated E degrees values more positive than that of the calculated Co(II)/Co(I) couple of B(12). Thus, cob(I)alamin is expected to reduce these base-off vinyl-Cbls. Heterolytic cleavage of the Co-C bonds is much more favorable than homolysis (>21 kcal/mol) and is significantly more exergonic when coupled to chloride elimination.     

Cobalt-Catalyzed Enantioselective Hydroamination of Arylalkenes with Secondary Amines

Catalytic asymmetric hydroamination of alkenes with Lewis basic amines is of great interest but remains a challenge in synthetic chemistry. Here, we developed a Co-catalyzed asymmetric hydroamination of arylalkenes directly using commercially accessible secondary amines. This process enables the efficient access to valuable α-chiral tertiary amines in good to excellent yields and enantioselectivities. Mechanistic studies suggest that the reaction includes a CoH-mediated hydrogen atom transfer (MHAT) with arylalkenes, followed by a pivotal catalyst controlled S_N2-like pathway between in situ generated electrophilic cationic alkylcobalt(IV) species and free amines. This radical-polar crossover strategy not only provides a straightforward and alternative approach for the synthesis of enantioenriched α-tertiary amines, but also underpins the substantial opportunities in developing asymmetric radical functionalization of alkenes with various free nucleophiles in oxidative MHAT catalysis.     

Reduction‐Labile Organo‐cob(III)alamins via Cob(II)alamin: Efficient Synthesis and Solution and Crystal Structures of [(Methoxycarbonyl)methyl]cob(III)alamin

An efficient synthesis of Coβ‐[(methoxycarbonyl)methyl]cob(III)alamin ( 6 ) is reported as an example of a new method for the preparation of some easily reducible organo‐cob(III)alamins via the alkylation of cob(II)alamin. The procedure represents a considerable improvement compared to earlier methods that were based on an alkylation of cob(I)alamin. Thus, aquacob(III)alamin chloride ( 5 ⁺?Cl) was reduced to cob(II)alamin ( 4 ), either by controlled potential electrolytic reduction or with an excess of sodium formate as reducing agent. The solution of 4 was then treated with an excess of methyl bromoacetate while being reductively poised potentiostatically or kept reduced by the formate, to give crystalline 6 in a yield of up to 91%. The structure of 6 in aqueous solution was mainly established by the completely assigned ¹H‐ and ¹³CNMR spectra (Table 1). The NOE data (Table 2) were best rationalized by the presence of a single main conformation of the (methoxycarbonyl)methyl ligand. Single crystals of 6 were obtained by crystallization from an aqueous solution, and the crystal structure was determined by X‐ray analysis at cryotemperatures. The NMR and crystallographic data of 6 indicated similar structures in aqueous solution and in the crystal with the (methoxycarbonyl)methyl ligand preferring a ‘southern' orientation in each case.     

Catalytic oxyalkylation of alkenes with alkanes and molecular oxygen via a radical process using N-hydroxyphthalimide

A novel catalytic method for the radical addition of alkanes and molecular oxygen to electron-deficient alkenes was achieved by the use of N-hydroxyphthalimide (NHPI) combined with a Co species as the catalyst. This reaction is referred to as oxyalkylation of alkenes with alkanes and O(2). For instance, the reaction of 1,3-dimethyladamantane with methyl acrylate under molecular oxygen in the presence of catalytic amounts of NHPI and Co(acac)(3) at 70 degrees C for 16 h gave oxyalkylated products in 91% yield. Other alkenes such as fumarate and acrylonitrile also serve as good acceptors of alkyl radicals and O(2) to afford the corresponding adducts in high yields. The generality of the present reaction was examined between various alkanes and alkenes under dioxygen. The behavior of Co ions during the reaction course was discussed. The present reaction involves (i) an alkyl radical generation via hydrogen abstraction of alkane by phthalimide N-oxyl generated in situ from NHPI and O(2) assisted by Co(II), (ii) the addition of the resulting alkyl radical to an electron-deficient alkene to form an adduct radical, (iii) trapping of the adduct radical by O(2) yielding a hydroperoxide, and (iv) the decomposition of the hydroperoxide by Co ions to form an adduct in which a hydroxy or a carbonyl function is incorporated.     

Interaction between super-reduced cobalamin and selenite

The kinetics of the reaction between the two-electron reduced form of cobalamin (super-reduced cobalamin, cob(I)alamin, or Cbl(I)) and sodium selenite in an alkaline medium is studied spectrophotometrically. It is shown that the selenite rapidly oxidizes Cbl(I) to cob(II)alamin (Cbl(II)). It is established that the active form of the oxidant is the protonated selenite anion (HSeO₃^-), which receives six electrons during the reaction and transforms into HSe^–. The reactions of cob(I)alamin oxidation by selenite and sulfite are compared.     

the Mechanism of the Oxidation of Cob(I)alamins

Abstract

Spectroelectrochemical investigations of the reoxidation sequence of the reduced cob(I)alamin to the oxidized cob(III)alamin show that two different cob(II)alamin intermediates are formed during the processes which appear to correlate to base-on and base-off cob(II)-alamin species.     

Thermal Methyl-Group Transfer between Methylcobalt(III) Corrinates and Cobalt(II) Corrinates. Equilibration Experiments with Heptamethyl Cobyrinates and Cobalamins

Separate neutral aqueous solutions of either (a) methylcob(III)alamin ( 2 ) and (heptamethyl cob(II)yrinate) perchlorate ( 3 ) or of b) cob(II)alamin ( = vitamin B_12r; ( 4 ) and [Coβ-methyl(heptamethyl cob(III)yrinate)] perchlorate ( 5 ) equilibrated thermally at r.t. according to 2 + 3 ? 4 + 5 . The corresponding equilibrium constant K_e was determined (K_e = 0.63 ± 0.15). This equilibration experiment indicates that the coordination of the nucleotide function in methylcob(II)alamin ( 2 ) hardly affects the thermodynamics of the Co? C bond homolysis in aqeous solution when compared to nucleotide-free methylcorrinoids such as 5 .     

Determination of hydroxyalkyl derivatives of cobalamin (vitamin B12) using reversed phase high performance liquid chromatography with electrospray tandem mass spectrometry and ultraviolet diode array detection.

Electrospray ionization tandem mass spectrometry (ESI-MS/MS) and ultraviolet diode array detection (UV-DAD), coupled on-line to reversed phase high performance liquid chromatography (HPLC), was used for the characterization of hydroxyalkyl derivatives of cob(I)alamin. The reduced form of vitamin B12, cob(I)alamin, denoted a supernucleophile due to its high nucleophilic strength, has shown promise as an analytical tool in studies of electrophilically reactive compounds in vitro and in vivo. A method for analysis of DNA-phosphate adducts was developed earlier utilizing the supernucleophilicity of cob(I)alamin to transfer alkyl groups from the phosphotriester configuration in DNA, with the formation of a Co-substituted alkyl-cobalamin (alkyl-Cbl) complex. For the purpose of identification and quantification of alkyl-Cbls at high sensitivity, an MS/MS method has been developed with application to a number of 2-hydroxyalkyl-cobalamins (OHalkyl-Cbls). The precursor oxiranes were reacted with cob(I)alamin, followed by clean-up and mass spectrometric analysis of the resulting OHalkyl-Cbls. It was found that ionization was highly dependent on solvent composition. By using acetonitrile/water/trifluoroacetic acid (TFA) (eluent I), the base peak was the doubly protonated molecule [M + 2H](2+), whereas acetonitrile/water/1-methylpiperidine (eluent II) yielded the singly protonated molecule [M + H](+) as the base peak. Excellent separation was obtained with eluent II, with good separation between stereoisomers, thus enabling the characterization of these by means of UV spectra. Limits of quantitation for 2-hydroxypropyl-cobalamin (OHPr-Cbl) were 0.2 and 2 pg/microL (or 0.1 and 1 fmol/microL) using selected ion recording (SIR) with eluent I and II, respectively. The obtained detection level should be sufficient for analysis of alkyl-Cbls from a wide range of toxicological applications.     

A mild and efficient palladium–triethylsilane system for reduction of olefins and carbon–carbon double bond isomerization

The versatility of palladium(II) acetate and palladium on activated charcoal catalysts with triethylsilane has been investigated in the hydrogenation and the isomerization of carbon–carbon double bond of 1‐alkenes. The reduction of 1‐alkenes was carried out in the presence of triethylsilane, ethanol and a catalytic amount of palladium(II) acetate or palladium on activated charcoal, at room temperature. This facile and efficient method affords high yields for hydrogenation of unsaturated alkenes to the corresponding alkanes. Then the carbon–carbon double bond isomerization of 1‐alkenes was tested using the same catalysts in the absence of solvent. The system palladium(II) acetate‐triethylsilane was found to be more effective compared with palladium on an activated charcoal–triethylsilane system at room temperature, while comparable results were obtained at 50 °C for both catalysts. Copyright © 2006 John Wiley & Sons, Ltd.     

Tyrosine 89 accelerates Co-carbon bond homolysis in methylmalonyl-CoA mutase

The contribution of the active-site residue, Y89, to the trillion-fold acceleration of Co-carbon bond homolysis rate in the methylmalonyl-CoA mutase-catalyzed reaction has been evaluated by site-directed mutagenesis. Conversion of Y89 to phenylalanine or alanine results in a 10(3)-fold diminution of k(cat) and suppression of the overall kinetic isotope effect. The spectrum of the enzyme under steady-state conditions reveals the presence of AdoCbl but no cob(II)alamin. Together, these results are consistent with homolysis becoming completely rate determining in the forward direction in the two mutants and points to the role of Y89 as a molecular wedge in accelerating Co-carbon bond cleavage.     

Visible-Light Photoredox-Catalyzed Remote Difunctionalizing Carboxylation of Unactivated Alkenes with CO2

Remote difunctionalization of unactivated alkenes is challenging but a highly attractive tactic to install two functional groups across long distances. Reported herein is the first remote difunctionalization of alkenes with CO₂. This visible-light photoredox catalysis strategy provides a facile method to synthesize a series of carboxylic acids bearing valuable fluorine- or phosphorus-containing functional groups. Moreover, this versatile protocol shows mild reaction conditions, broad substrate scope, and good functional-group tolerance. Based on DFT calculations, a radical adds to an unactivated alkene to smoothly form a new carbon radical, followed by a 1,5-hydrogen atom-transfer process, the rate-limiting step, generating a more stable benzylic radical. The reduction of the benzylic radicals by an Ir^II species generates the corresponding benzylic carbanions as the key intermediates, which further undergo nucleophilic attack with CO₂ to generate carboxylates.     

Cob(I)alamin als Katalysator. 6. Mitteilung [1]. Bildung und Fragmentierung von Alkylcobalaminen,ein Gleichgewichtsprozess zwischen nukleophiler Addition und reduktiver Fragmentierung

Cob(I)alamin as Catalyst. 6. Communication [1]. Formation and Fragmentation of Alkylcobalamins: the Nucleophilic Addition – Reductive Fragmentation Equilibrium Isolated olefines can be saturated using catalytic amounts of cob(I)alamin in aqueous acetic acid; as electron source an excess of zinc dust is added to the solution containing the homogeneous catalyst. During this overall hydrogenation of isolated double bonds intermediate alkylcobalamins are formed (compare e.g. Schemes 2, 4, 5, 7 and 12). Clear evidence is presented that the nucleophilic attack on the isolated double bond is carried out by cob(I)alamin and not by cob(II)alamin also present in the system (see Scheme 3b and 3c). As this catalytic saturation of olefins depends on the pH of the solution, characterized by a slow reaction at pH = 7.0 compared to the same reduction in aqueous acetic acid (see Scheme 2, 2 → 4 , and Scheme 3a), it is reasonable to accept the participation of an electrophilic attack by a proton during the generation of alkylcobalamins. – We use the term nucleophilic addition to describe the formation of alkylcobalamins from a proton, an olefin and cob(I)alamin (compare Schemes 4–7 and 12). A special sequence of experiments showed the nucleophilic addition to be regioselective. Preferentially the higher substituted alkylcobalamin revealed to be produced. Therefore, the nucleophilic addition of cob(I)alamin follows the Markownikoff rule (compare chap. 4: formation and fragmentation of β-hydroxyalkylcobalamins). Under the reaction conditions applied the intermediate alkylcobalamins can be present in base-on and base-off forms. They are known to exist as octahedral complexes and might also be stable to some extent as tetragonal-pyramidal species. In addition the base-off forms can partially be protonated at the dimethylbenzimidazole moiety in aqueous acetic acid (compare Scheme 12). From this equilibrium of intermediate alkylcobalamins three modes of decay disclosed to be possible: (i) The reductive fragmentation leading to an olefin, a proton, and cob(I)alamin is the formal retro-reaction of the nucleophilic addition (see Schemes 2, 4 and 6–12). This equilibrium of an associated alkylcobalamin and the corresponding dissociation products revealed to be a fast process compared to the reductive cleavage of the Co, C-bond cited below (s. (iii)). (ii) As the second reaction pattern an oxidative fragmentation producing an olefin, a hydroxy anion (or water, respectively) and cob (III)alamin has been observed (see Schemes 7, 8, 10 and 12). (iii) The slow reductive cleavage of the Co, C-bond, initiated by addition of electrons (see [1a] [24]), was the third reaction path observed (see Schemes 2, 4–8 and 10–12). – The stereochemistry of the three transformations originating from the intermediate alkylcobalamins is unknown up to now. The antiperiplanar pattern of the fragmentation reactions presented in the Schemes has been chosen arbitrarily (see e.g. Scheme 12).