Addition-elimination sequence

Generally, the reactions of halopyrazines and haloquinoxalines with nucleophiles are believed to proceed by way of addition/elimination sequences, although there are clear-cut examples where this is not the case (see Section 2.14.2.2) and, consistent with a mechanism which involves bond forming, rather than bond breaking, reactions in the rate-determining step, fluoro derivatives are considerably more reactive ca. xlO ) than the corresponding chloro derivatives. 

The 3-substituents in 3-nitro- and 3-phenylsulfonyl-2-isoxazolines were displaced by a variety of nucleophiles including thiolate, cyanide and azide ions, ammonia, hydride ions and alkoxides. The reaction is pictured as an addition-elimination sequence (Scheme 54) (72MI41605, 79JA1319, 78JOC2020). 

Methyl pyrrole-l-carboxylate (14) and hot dimethyl acetylenedi-carboxylate give trimethyl pyrrole-1,3,4-tricarboxyIate (15) and acetylene, presumably through the addition-elimination sequence shown. Dimethyl acetylenedicarboxylate and 1-methylpyrrole com-... 

Though dental afflictions constitute a very significant disease entity, these have received relatively little attention from medicinal chemists. (The fluoride toothpastes may form an important exception.) This therapeutic target Is, however, sufficiently Important to be the focus of at least some research. A highly functionalized piperazine derivative that has come out of such work shows prophylactic activity against dental caries. Condensation of the enol ether 1 of thiourea with ji-pentylisocyanate gives the addition product 1J. Reaction of this with diamine 78, derived from piperazine, leads to substitution of the methylthio moiety by the primary amine, in all likelihood by an addition-elimination sequence. There is thus obtained ipexidine (79). ... 

The majority of analgesics can be classified as either central or peripheral on the basis of their mode of action. Structural characteristics usually follow the same divisions the former show some relation to the opioids while the latter can be recognized as NSAlD s. The triamino pyridine 17 is an analgesic which does not seem to belong stmcturally to either class. Reaction of substituted pyridine 13 (obtainable from 12 by nitration ) with benzylamine 14 leads to the product from replacement of the methoxyl group (15). The reaction probably proceeds by the addition elimination sequence characteristic of heterocyclic nucleophilic displacements. Reduction of the nitro group with Raney nickel gives triamine 16. Acylation of the product with ethyl chlorofor-mate produces flupirtine (17) [4]. 

Pefloxacin (33) is the N-methyl analogue of norfloxacin (58) and is at least partly converted to it by metabolic enzymes in vivo. It has been launched in France for the treatment of a number of infections including those caused by sensitive strains of Pseudomonas aeruginosa. It can be synthesized starting with the Gould-Jacobs reaction of 3-chloro-4-fluoroaniline (28) and diethyl ethoxymethylenemalonate in an addition-elimination sequence leading to 29 which undergoes... 

The net effect of the addition/elimination sequence is a substitution of the nucleophile for the -Y group originally bonded to the acyl carbon. Thus, the overall reaction is superficially similar to the kind of nucleophilic substitution that occurs during an Sn2 reaction (Section 11.3), but the mechanisms of the two reactions are completely different. An SN2 reaction occurs in a single step by backside displacement of the Leaving group a nucleophilic acyl substitution takes place in two steps and involves a tetrahedral intermediate. 

Two pathways for the reaction of sulfate radical anion with monomers have been described (Scheme 3.81).252 These are (A) direct addition to the double bond or (B) electron transfer to generate a radical cation. The radical cation may also be formed by an addition-elimination sequence. It has been postulated that the radical cation can propagate by either cationic or a radical mechanism (both mechanisms may occur simultaneously). However, in aqueous media the cation is likely to hydrate rapidly to give a hydroxyelhyl chain end. 

Table 2 surveys different types of addition-elimination sequences (equation 29). 

A5-hexenyl substituent, extensive cyclization occurs to yield the cyclopentylcarbinyl product from the yields of uncyclized and cyclized products for A5-hexenylmercury chloride, the rate constants for equation 50 have been estimated (vide supra). The SH2 reaction 49 has also been invoked to be the key step in the alkylation of -substituted styrenes by a free-radical addition-elimination sequence, namely96... 

The fragmentation of alkoxyl radicals is especially favorable because the formation of a carbonyl bond makes such reactions exothermic. Rearrangements of radicals frequently occur by a series of addition-fragmentation steps. The following two reactions involve radical rearrangements that proceed through addition-elimination sequences. 

RajanBabu et al. have described an addition-elimination sequence employing vinyl stannanes for the preparation of homoallylic alcohols containing 5-membered rings [104],... 

Hydrolysis of diphenyl phosphorochloridate (DPPC) in 2.0 M aqueous sodium carbonate is also believed to be a two-phase process. DPPC is quite insoluble in water and forms an insoluble second phase at the concentration employed (i.e. 0.10 M). It seems highly significant that the hydrophobic silicon-substituted pyridine 1-oxides (4,6,7) are much more effective catalysts than hydrophilic 8 and 9. In fact, 4 is clearly the most effective catalyst we have examined for this reaction (ti/2 < 10 min). Since derivatives of phosphoric acids are known to undergo substitution reactions via nucleophilic addition-elimination sequences 1201 (Equation 5), we believe that the initial step in hydrolysis of DPPC occurs in the organic phase. Moreover, the... 

Nitroalkenes are generally prepared by the substitution reaction of [i-nitro sulfides and sulfoxides with a variety of carbon nucleophiles via an addition-elimination sequence. This method is particularly useful for the preparation of cyclic nitroalkenes (Eq. 4.100).126... 

A more elaborate spiroquinolizidine unit 463 was obtained by simply heating a basic thiophenoxide solution of thioether 461, presumably by addition-elimination of thiophenoxide to give 462, which then cyclized by a second addition-elimination sequence involving the piperidine nitrogen atom, giving 463, an advanced intermediate, in a total synthesis of ( )-halichlorine (Scheme 110) <2004PNAS12079>. 

Reaction between 2,8-dichloro derivative 115 and sodium azide in DMSO does not lead to 3,9-diazido derivative 116 expected by direct displacement. Instead, the reaction gives isomeric 3,9-diazide 117, presumably by an addition-elimination sequence <1995JOC6110, 1995HAC391>. Compound 116 is available by treatment of tetra-nitro derivative 90 (z-TACOT) with LiN3 in DMSO (Scheme 11) <1967JA2626>. 

Liebeskind and associates converted 3,4-diisopropyl squarate (97) to stannylcyclobutenedione 98 via a 1,4-addition-elimination sequence. 98 was then coupled with 2-iodothiophene to afford substituted cyclobutenedione 99 [85]. In another case, 3-lithioquinuclidin-2-ene, generated from the Shapiro reaction of 3-quinuclidinone (100), was quenched with Bu3SnCl to afford a unique enamine stannane 101. The Stille reaction of stannane 101 and 5-bromo-2-formyl-thiophene then furnished 3-thienylquinuclidine 102 [86]. 

From a chemical point of view, amide and ester bonds have comparable structural and spectroscopic features and are hydrolyzed by the same general mechanism, i.e., a nucleophilic acyl substitution involving an addition-elimination sequence (see Chapt. 3). However, in a given structure, the amide... 

Although the reaction responsible for the generation of the hydride is not specified, it is assumed that it arises from a disproportionation of iron carbonyl complexes. The hydride presumably adds after ir-complexing to form the c-bonded complex which then splits out the metal hydride in either direction. The ir-complexed olefin may then be displaced by another olefin or undergo another hydride addition-elimination sequence. The second path involves olefin complexing with the deficient Fe(CO)3 species and formation of a jr-allyliron hydride intermediate ... 

It was mentioned above that acetalic nitroxyl radicals produced by addition of a-alkoxyalkyl radicals to tetranitromethane (TNM) undergo a spontaneous heterolysis with the carbon center being oxidized and TNM reduced (to nitro-form anion (NF ) and NOj). In order to see the addition-elimination sequence with acyclic a-alkoxyalkyl radicals there have to be two (electron-withdrawing relative to methyl) hydrogens at Q. Even one alkyl group at Q is sufficient to make khs > 10 s and therefore too fast to measure. If, however, an alkyl group which is inductively deactivated is introduced at Q, the k values fall in the... 

If an experiment of this type is performed with an aqueous solution saturated with isobutene and containing 20 mM Cl, a unimolecular rise of conductance of the solution occurs after production ( < 1 ps) of SOi." radicals. At 20 °C the rate constant of this conductance change, which is independent of pH between 4 and 11, is 3.1 x 10" s [46]. These results are explained by reactions (27)- 30), (29) and (30) constituting the actual addition/elimination sequence ... 

However, if there is another leaving group in this molecule, then this may be lost instead, so that overall the reaction becomes a nucleophilic substitution, though really it should be regarded as an addition-elimination sequence, since the... 

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