Nucleophilic substitution stereospecificity

Overall the stereospecificity of this method is the same as that observed m per oxy acid oxidation of alkenes Substituents that are cis to each other m the alkene remain CIS m the epoxide This is because formation of the bromohydrm involves anti addition and the ensuing intramolecular nucleophilic substitution reaction takes place with mver Sion of configuration at the carbon that bears the halide leaving group... 

Markovnikov s rule is also usually followed where bromonium ions or other three-membered rings are intermediates. This means that in these cases attack by W must resemble the SnI rather than the Sn2 mechanism (see p. 461), though the overall stereospecific anti addition in these reactions means that the nucleophilic substitution step is taking place with inversion of configuration. 

The mechanistic aspects of nucleophilic substitution reactions were treated in detail in Chapter 4 of Part A. That mechanistic understanding has contributed to the development of nucleophilic substitution reactions as important synthetic processes. Owing to its stereospecificity and avoidance of carbocation intermediates, the Sw2 mechanism is advantageous from a synthetic point of view. In this section we discuss... 

A novel route to 3,4-disubstituted piperidines 206 via ring transformation of 2-(haloalkyl)azetidines 207 is shown below. During these reactions, bicyclic azetidinium intermediates are formed and then ring opened by a variety of nucleophiles generating stereospecific substituted piperidines in excellent yields <06OLl 105>. 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

Stereospecific nucleophilic substitution in chiral ion—dipole complexes. Chiral molecules can be discriminated in the Cl source of a CIMS instmment by specific ion-molecule reactions induced by chiral reagent gas. This method has been applied with success to distinguish between enantiomeric and diastereomeric forms of menthols ((lR,2S,5R)-(— )-14, (lS,2R,5S)-(+)-14, and (lR,2R,5S)-(—)-14 in Scheme 11) through the nucleophilic displacement of their hydroxyl group by (5)-2-amino-l-butanol Self-protonation of As... 

In another report of Singh and Han [61], Ir-catalyzed decarboxylative amidations of benzyl allyl imidodicarboxylates derived from enantiomerically enriched branched allylic alcohols are described. This reaction proceeded with complete stereospecificity-that is, with complete conservation of enantiomeric purity and retention of configuration. This result underlines once again (cf. Section 9.2.2) that the isomerization of intermediary (allyl) Ir complexes is a slow process in comparison with nucleophilic substitution. 

F.K. Hamacher, FI.FI. Coenen, G. Stocklin, Efficient stereospecific synthesis of no-carrier-added 2-[ F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution, J. Nucl. Med. 27 (1986) 235-238. 

Walden inversion (Section 8.4) Originally, a reaction sequence developed by Paul Walden whereby a chiral starting material was transformed to its enantiomer by a series of stereospecific reactions. Current usage is more general and refers to the inversion of configuration that attends any bi-molecular nucleophilic substitution. 

Scheme 7.15] or S -type mechanism [Equation (7.9)]. Depending on the nature of the nucleophile and catalyst employed, the subsequent nucleophilic substitution of the metal can follow either via a-elimination [path A, Equations (7.8) and (7.9), Scheme 7.15], via an SN2 reaction (path B) or via an SN2 -type reaction (path C). For reasons of clarity, only strictly concerted and stereospecific SN2- or SN2 -anti-type mechanistic scenarios are shown in Scheme 7.15. The situation might, however, be complicated if, e.g., the initial S l -anti ionization event is competing with an Sn2 -syn reaction. Erosion in stereo- and regioselectivity can be the result of these competing reactions. Furthermore, fluxional intermediates such as 7t-allyl Fe complexes are not shown in Scheme 7.15 for reasons of clarity. These intermediates are known for a variety of late transition metal allyl complexes and will be referred to later. Moreover, apart from these ionic mechanisms, radicals might also be involved in the reaction. So far no distinct mechanistic study on allylic substitutions has been published.

In fact, Hughes found that the rate of racemization was twice the rate of incorporation of radioactive iodide. This experiment provided strong evidence for the belief that bimolecular nucleophilic substitution proceeds stereospecifically with inversion of configuration. 

Scheme4.3. Possible mechanism for stereospecific radical nucleophilic substitutions [15],...

S. S. Shaik, A. C. Reddy, A. Ioffe, J. P. Dinnocenzo, D. Danovich, J. K. Cho, J. Am. Chem. Soc. 117, 3205 (1995). Reactivity Paradigms. Transition State Structures, Mechanisms of Barrier Formation, and Stereospecificity of Nucleophilic Substitutions on a-Cation Radicals. 

Fig. 10.48. Nucleophilic substitution II on an acceptor-substituted alkene with a leaving group in the /3-position (possibility for preparing the starting materials Figure 13.25). Stereospecifity occurs in the reaction pair shown.

Nucleophilic substitution of a,/3-epoxysilanes followed by the Peterson elimination is valuable for the stereoselective synthesis of alkenes.3 The reactions with lithium phenylsulfide and diphenylphosphide form alkenyl sulfides and alkenylphosphines, respectively, in a stereospecific manner. 7-Metallo-a,/ -epoxysilanes are isomerized to a-siloxyallylmetals by anionic ring opening and subsequent Brook rearrangement (Equation... 

The Sn2 displacement is a good example of a stereospecific reaction one in which different stereoisomers react to give different stereoisomers of the product. To study the mechanism of a nucleophilic substitution, we often look at the product to see if the reaction is stereospecific, with inversion of configuration. If it is, the Sn2 mechanism is a good possibility, especially if the reaction kinetics are second order. In many cases (no asymmetric carbon or ring, for example), it is impossible to determine whether inversion has occurred. In these cases, we use kinetics and other evidence to help determine the reaction mechanism. 

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