SN2-like intermediates

It is well known that Sn2 reactions occur with inversion of configuration. Several attempts have been made to isolate and observe true SN2-like intermediates. Ions like CH3CI2 and related anion adducts are known in the gas phase. However, (TI.Cl is indeed only the CH3CI solvated chloride ion (164). Compounds such as CCls" are also known as stable species in the condensed state. However, it was shown that CCU is an analog of CV, with the pseudohalide group replacing a chlorine atom (165). 

Scheme 10. Mechanislic possibililies for PF condensalion. Mechanism a involves an SN2-like attack of a phenolic ring on a methylol. This attack would be face-on. Such a mechanism is necessarily second-order. Mechanism b involves formation of a quinone methide intermediate and should be Hrst-order. The quinone methide should react with any nucleophile and should show ethers through both the phenolic and hydroxymethyl oxygens. Reaction c would not be likely in an alkaline solution and is probably illustrative of the mechanism for novolac condensation. The slow step should be formation of the benzyl carbocation. Therefore, this should be a first-order reaction also. Though carbocation formation responds to proton concentration, the effects of acidity will not usually be seen in the reaction kinetics in a given experiment because proton concentration will not vary.

When a sulfonate ester possessing this type of chirality was converted to a sulfone with a Grignard reagent (10-129), inversion of configuration was found. This is not incompatible with an intermediate such as 147 but it is also in good accord with an Sn2 like mechanism with backside attack. 

With respect to B, this is an S l type process. If inversion occurs at B, it is likely that the first two steps are concerted, that a carbocation is not an intermediate, and that the process is Sn2 like ... 

The generalized Woodward-Hoffmann rule suggests that a synchronous addition of disulfonium dications at the double C=C bond of alkenes would be a thermally forbidden process and so would be hardly probable. Simulation of the frontal attack by ethylene on l,4-dithioniabicyclo[2.2.0]hexane 115 gave no optimal structure of an intermediate complex. On the other hand in the lateral approach of the reactants, orbital factors favor attack of the double bond by one of the sulfonium sulfur atoms of the dication. This pattern corresponds to SN2-like substitution at sulfur atom as depicted in Figure 5. Using such a reactant orientation, the structure of intermediate jc-complex was successfully optimized. The distances between the reaction centers in the complex, that is, between the carbon atoms of the ethylene fragment and the nearest sulfur atom of the dication, are 2.74 and 2.96 A, respectively. 

The determination of the lifetime of the ionic intermediates using the azide-clock method has been however useful in showing that electrophilic addition of Br2 can occur, even through a fully concerted mechanism, definable as SN2-like. Bromination of cyclic enol ethers (glycals) 8-10 in methanol in the presence of... 

The formation of the bridged intermediate has been represented as an SN2-like displacement of the leaving group from the sulfenyl sulphur of 85116, or alternatively, as reported in equation 90 in agreement with the addition of other electrophiles to alkenes, it has been proposed that the reaction involves the initial formation of jr-complex 86 in a rapid equilibrium with the reagents76. 

Cyclization. A second kind of reaction is represented by the conversion of S-adenosylmethionine to aminocyclopropanecarboxylic acid, a precursor to the plant hormone ethylene (see Chapter 24).159 The quinonoid intermediate cyclizes with elimination of methylthioadenosine to give a Schiff base of the product (Eq. 14-27).160-161a The cyclization step appears to be a simple SN2-like reaction.162... 

The stereochemical outcome of this transformation deserves special comment. Based on established mechanistic grounds, the likely intermediate in this process is the transient 1,2-epoxide, 107 (Eq. 15). Reaction with nucleophiles occurs exclusively at C-l as a result of powerful electronic effects, as evidenced by the exclusive formation of 1-azidoad-ducts 104 and 105. However, the resulting stereochemistry of the 1-sub-stituted-2-hydroxy adducts depends greatly on the reaction conditions. For example, Rebek reported that a cis-1 -methoxy-2-hydroxy adduct was isolated as the major product when bromohydrin 106 was exposed to basic reaction conditions (NaOMe/MeOH).80 In this case the product cis/trcms ratio was found to be inversely proportional to the base concentration, a fact suggesting that the minor trans-adduct arose directly via Sn2 attack on the epoxide 107. To explain the formation of the cis-adduct,... 

The details of the cupric salt reaction with the palladium adduct are not clear. Exchange to form a cupric alkyl is one possibility or complex formation,"probably with chloride bridges between the palladium adduct and cupric chloride, may occur with subsequent anion shift from palladium to carbon or perhaps an Sn2 displacement of the complex metal group by an anion may occur. Rearrangements producing 1,3 and 1,4 substituted products from linear olefins have also been observed. For example, 1-butene produced several percent of 1,3- and 1,4-chloro acetates and diacetates under the reaction conditions used 16>. "Hydrido-palladium acetate or chloride" -complexes would seem to be likely intermediates in these arrangements. 

In general, one speaks of a neighboring group effect only when the cyclic and usually positively charged intermediate cannot be isolated but is subject to an SN2-like ring opening by the... 

P selectivity. Crich and coworkers proposed that, under preactivation conditions, the oxocarbenium ion is trapped by a triflate anion to form the more stable a-triflate 65. After addition of the acceptor, the a-triflate intermediate can then be displaced in an SN2-like manner to afford a p-mannoside product (68). The formation of a-glycosyl triflates was confirmed by II, 13C, and 19F NMR analyses of the activated mannosyl donor recorded at low temperature [37], The experimentally determined KIE is approximately 1.12, which is consistent with an oxocarbenium-like TS [38], It was hypothesized that the a-triflate converts into the contact ion pair 66 in which the triflate anion remains at the a face or that an exploded TS is formed where the nucleophile is loosely associated with the oxocarbenium ion as the triflate departs [39,40], The a product 69 can be explained by the formation of the solvent-separated ion pair 67 where the counterion is solvated and facial selectivity is lost. 

For reactions which do not proceed via radical intermediates, the question of detail remains does the polar substitution take place via an SN2-like substitution at the halogen, or is there an intermediate - an ate complex Gilman was the first to suggest a mechanism for halogen-... 

It is probable that methyl transferase reactions proceed by nucleophilic attack on S-adenosylmethionine94 and may involve an SN2-like transition state.95 Thus, inversion of configuration as observed in indolmycin biosynthesis indicates that an odd number of nucleophilic displacements occurs and suggests that the methyl group is transferred directly from donor to (112), i.e. without generation of a methylated-enzyme intermediate.92 The combined results are summarized in Scheme 11. 

One reason for believing this is simply the anticipated difficulty of forming a highly unstable intermediate in which an electronegative element like nitrogen has only a sextet of electrons. Such a particle should be even less stable than primary carbo-cations, and those, we know, are seldom formed reaction takes the easier, Sn2-like path. Another reason is the effect of structure on rate of reaction. Let us examine this second reason. 

Bimolecular nucleophilic substitution reactions (Sn2) involve pentacoordinate carbon in their transition state. Whereas pentacoordinate CHs -like intermediates of Se2 reactions represent only an eight-electron system around the carbocationic center involving 3c-2c bonding (octet rule is obeyed), an Sn2 reaction intermediate would represents a 10-electron system involving three-center, four electron (3c-4e) bonding (a lO-C-5 species). This, however, is an unstable situation since carbon cannot accommodate 10 electrons in its valence shell. A simple picture of typical molecular orbitals in 3c-4c bonding is shown in Figure 6.9. 

Regarding the reaction mechanism, Whitesides and coworkers also postulated that the presence of a j8-nitrilium ion was the source of stereocontrol. In their proposed mechanism, the xanthate 27 initially reacts with the PST promoter to form 35 (Scheme 13). Subsequent loss of 36 leads to the oxocarbenim intermediate 31. Attack by acetonitrile is presumed to occur from the less hindered a face and leads to the presumably thermodynamically more favorable equatorial nitrilium ion 37 because of the reverse anomeric effect [13,14]. However the equatorial nitrilium ion is believed to be in equilibrium with the more reactive fi species 32. Acetonitrile is then displaced from this species by the glycosyl acceptor in an SN2-like maimer for form the a-glycosidic linkage in compound 38... 

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