Vinylic SN2 reactions

In 1991, we reported that a nucleophilic vinylic substitution of (E)-fi-alkylvinyl-AModanes with halides (BuN4X, X = C1, Br, I) in dichloromethane, methanol, or acetonitrile at room temperature proceeds with exclusive inversion of configuration [Eq. (100)] [176,177]. This is the first clear example of a vinylic Sn2 reaction. This reaction competes with an alkyne-forming reductive syn /3-elimination. 

Nucleophiles that undergo vinylic SN2 reaction involve sulfides, selenides [178], carboxylic acids [179], amides [180],thioamides [181],andphosphorose-lenoates [Eq. (102)] [182]. All of these reactions proceed with exclusive inversion of configuration. These nucleophiles are only weakly basic or non-basic. More basic nucleophiles would result in a facile a-elimination of vinyl-A3-iodanes generating alkylidene carbenes instead of the vinylic SN2 reaction. 

Kinetic and spectroscopic studies of reactions of several ( )-/J-alkyl-vinyl(phenyl)iodonium tetrafluorob orates with tetrabutylammonium chloride indicate that the vinyliodonium chlorides, generated by anion exchange, are present in equilibrium with the corresponding vinyl(chloro)iodanes (Scheme 48) [140]. Both species undergo vinylic Sn2 reactions with chloride ion, and although the chloroiodanes are less reactive, they are by far the dominant species at equilibrium and account for most of the (Z)-l-chloroalkene production. 

Vinylic Sn2 reactions of ( )-/ -alkylvinyl(phenyl)iodonium tetrafluorobo-rates with such weakly basic nucleophiles as V, N-dialkyl formamides, thioamides, thioureas, and heterocyclic thiols have recently been documented, examples of which are shown in Scheme 49 [141,142]. 

Vinylic SN2 reactions are discussed on p. 198. Here, we restrict ourselves to nucleophilic susbstitutions at saturated centers. Aromaticity criteria then strongly disfavor retention of configuration. Indeed, the transition state leading to retention, 43, resembles a four-electron (two from the nucleophile and two from the CY bond) antiaromatic annulene. 

The previous study might seem to be a theoretician s amusement, of no practical value. This is not true, as we will see when analyzing why vinylic SN2 reactions generally proceed with retention of configuration. 

Although nor shown in the preceding reactivity order, vinylic halides (R2C=CRX) and aryl halides are unreactive toward Sn2 reaction. This lack of reactivity is probably due to steric factors, because the incoming nucleophile... 

Alkylation reactions are subject to the same constraints that affect all Sn2 reactions (Section 11.3). Thus, the leaving group X in the alkylating agent R—X can be chloride, bromide, iodide, or tosylate. The alkyl group R should be primary or methyl, and preferably should be allylic or benzylic. Secondary halides react poorly, and tertiary halides don t react at all because a competing E2 elimination of HX occurs instead. Vinylic and aryl halides are also unreactive because backside approach is sterically prevented. 

Table 2. Some Examples of SN2 Reactions of Vinyloxiranes and Vinyl Acetals 1...

The attack of the nucleophile on the acceptor-substituted allene usually happens at the central sp-hybridized carbon atom. This holds true also if no nucleophilic addition but a nucleophilic substitution in terms of an SN2 reaction such as 181 — 182 occurs (Scheme 7.30) [245]. The addition of ethanol to the allene 183 is an exception [157]. In this case, the allene not only bears an acceptor but shows also the substructure of a vinyl ether. A change in the regioselectivity of the addition of nucleophilic compounds NuH to allenic esters can be effected by temporary introduction of a triphenylphosphonium group [246]. For instance, the ester 185 yields the phos-phonium salt 186, which may be converted further to the ether 187. Evidently, the triphenylphosphonium group induces an electrophilic character at the terminal carbon atom of 186 and this is used to produce 187, which is formally an abnormal product of the addition of methanol to the allene 185. This method of umpolung is also applicable to nucleophilic addition reactions to allenyl ketones in a modified procedure [246, 247]. 

If the potential leaving group is attached to unsaturated carbon, as in vinyl chloride or phenyl chloride, attack by nucleophiles is also extremely difficult, and these compounds are very unreactive in Sn2 reactions compared with simple alkyl halides. In these cases, the reason is not so much steric but electrostatic, in that the nucleophile is repelled by the electrons of the unsaturated system. In addition, since the halide is attached to carbon through an 5p -hybridized bond, the electrons in the bond are considerably closer to carbon than in an 5/ -hybridized bond of an alkyl halide (see Section 2.6.2). Lastly, resonance stabilization in the halide gives some double bond character to the C-Hal bond. This effectively strengthens the bond and makes it harder to break. This lack of reactivity is also tme for SnI reactions (see Section 6.2). 

The ET photochemistry of (IR, 35)-(+)-c/i-chrysanthemol (c/i-127) proceeds via nucleophilic attack of the internal alcohol function on the vinyl group with simultaneous or rapid replacement of an isopropyl radical as an intramolecular leaving group, forming 128. This reaction is a mechanistic equivalent of an Sn2 reaction the mode of attack underscores the major role of strain relief in governing nucleophilic capture in radical cations. 

The Sn2 reaction involves the attack of a nucleophile from the side opposite the leaving group and proceeds with exclusive inversion of configuration in a concerted manner. In contrast to the popular bimolecular nucleophilic substitution at the aliphatic carbon atom, the SN2 reaction at the vinylic carbon atom has been considered to be a high-energy pathway. Textbooks of organic chemistry reject this mechanism on steric grounds [175]. 

The transition state model (13) for the Sn2 reaction of a vinyl bromide was detected using laser flash photolysis.18... 

But most of the time we are chiefly concerned with getting the carbon nucleophile to add 1,4. The synthesis of the unsaturated ketone 62 makes two more points. While we cannot do Sn2 reactions on vinyl halides, they make good organo-lithium and copper reagents and, in the... 

When halogen atoms are attached to a vinylic carbon and also to one allylic to it, an SN2 process converts the vinylic halogen into an allylic one, while the formerly allylic one is replaced, and a new olefin is formed. Another SK2 attack at the new terminal vinylic carbon would result in the replacement of the original vinylic halogen. The vinylic halide can thus be exchanged in two consecutive SN2 reactions. 

While allylic SN2 reactions formally include a nucleophilic attack at the vinylic carbon atom, they are not discussed, except in cases when they have direct connection to the replacement of vinylic substituents. 

While bond formation and bond cleavage are simultaneous in SN2 reactions of saturated compounds, a vinylic carbon atom can become and remain four-covalent, bonded both to the nucleophile and to the leaving group. The initial difficulty in vinylic attack is therefore com-... 

In the addition-elimination routes, either via a carbanionic intermediate (I) or via a neutral adduct (II), the anionic nucleophile Nu or the neutral nucleophile NuH attacks the /3-carbon with the expulsion of X. In the a,/8-route (IV), the /9,/3-route (VI) and the /8, y- elimination-addition routes (VII), HX is eliminated in the initial step, and the nucleophile and hydrogen are then added to the intermediates. Substitution occurs also by heterolytic C—X bond cleavage in an SN1 process (X). Initial prototropy followed by substitution can also give vinylic substitution products (XII, XIV), as well as two consecutive Sn2 reactions (XV) where the leaving group leaves from an allylic position. 

The clue to the reaction is the polarity of the double bond. The lowest electron density is at the carbon linked to hydrogen, and is due to the strong inductive effect of the difluoromethylene groups and a slight effect of the vinylic chlorine. The attacking species, ethoxide anion, which is in an equilibrium with hydroxide ion in alcoholic potassium hydroxide, reacts in an SN2 reaction by joining the carbon bonded to hydrogen. The subsequent shift of the double bond facilitates ejection of fluorine as an anion and leads to an ether, compound O [77]. 

Vinyl and aryl halides generally do not undergo SN1 or Sn2 reactions. An SN1 reaction would require ionization to form a vinyl or aryl cation, either of which is less stable than most alkyl carbocations. An Sn2 reaction would require back-side attack by the nucleophile, which is made impossible by the repulsion of the electrons in the double bond or aromatic ring. 

CH3CH=CHC1 + NaNH2 — CH3C=CH + NH3 + NaCl Vinyl halides are quite inert toward SN2 reactions. 

Examples are the reaction of the nitronate anion 4.14 with p-nitrobcnzyl chloride 4.15, and the reaction of the pinacolone enolate 4.16 with bromo-benzene 4.17. The former might have been a straightforward SN2 reaction, but actually takes the SrnI pathway because the nitro groups make the electron transfer exceptionally easy. The latter cannot take place by a conventional Sk2 reaction, because aryl (and vinyl) halides are not susceptible to direct displacement, and the SrnI pathway overcomes this difficulty. 

The reaction of Pd complexes (such as Pd(PhsP)4) with organic halides and related compounds has been used to prepare a number of stable Pd alkyl and vinyl compounds. This reaction with alkyl halides has the characteristics of an Sn2 reaction. Primary halides react faster than secondary halides. Also, when a chiral halide is used, such as (X)-(-F)-benzyl-o -D chloride, the benzyl palladium product is formed with inversion of configuration at the benzylic carbon (equation 8). With vinylic halides, retention of configuration at the double bond is observed... 

Cyclic vinyloxiranes react with organocuprates with inversion of configuration (anti) and in a vinyl-ogous mode (equation 46), not by the expected Sn2 reaction that simple oxiranes are known to undergo. This subject has recently been summarize. ... 

SnI and Sn2 reactions occur only at sp hybridized carbon atoms. Now that we have learned about the mechanisms for nucleophilic substitution we ean understand why vinyl halides and aryl halides, which have a halogen atom bonded to an sp hybridized C, do not undergo nucleophilic substitution by either the S l or Sn2 mechanism. The diseussion here eenters on vinyl halides, but similar arguments hold for aryl halides as well. 

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