Nucleophilic addition-protonation

There is an alternate mechanism for halide replacement, following the sequence of nucleophile addition, protonation and elimination of HX (Scheme 9). In this pathway, the addition of the nucleophile need not be at the ipso position it can be ortho to halide leading to cine substitution or it can be at the meta or para positions, leading to tele substitution.69,70 The mechanism is the same for both cine and tele substitution and the different names reflect a differentiation in the IUPAC naming schemes. 

The nucleophilic addition-protonation mechanism is not confined to aqueous media. Reaction of phenylmethanesulfonyl-d2 chloride and triethylamine in the presence of triethylammonium fluoride gave PhCHDS02F132. Experiments with Et3NH + Cl and a mixture of the fluoride and chloride salts suggested that Cl was also capable of trapping the sulfene, but that the fluoride was more reactive toward sulfene by a factor of 4.6. 

The extension of the nucleophile addition/protonation sequence to an intramolecular reaction is shown in Scheme 9 and elegantly illustrates the potential for the rapid access to elaborate organic compounds with high selectivity. 

The sequential trans-addition of a carbon nucleophile and a carbon electrophile across an arene double bond in (arene)Cr(CO)3 was first reported in 1983 [35]. Since then this methodology has undergone extensive development, with recent efforts mainly directed towards enantioenriched products [36]. Anionic (cy-clohexadienyl)Cr(CO)3 complexes are very soft nucleophiles and this places restrictions on the electrophiles that can be used in this sequence. Specifically these reactions are successful when carbanion dissociation from the intermediate anionic cyclohexadienyl complex is slow compared to the reaction with the carbon electrophile. The sequential addition is usually carried out as a one-pot reaction and the proposed reaction sequence is that shown in Scheme 11. In contrast to the nucleophile addition/protonation sequence, products form with excellent 1,2-regioselectivity. It is likely that this is due to an irreversible transfer of the acyl, allyl, or propargyl group to one of the two termini of the cyclohexadienyl ligand. 

What is the mechanism of the ionic addition of these milder reagents to the carbon-oxygen double bond Two pathways can be formulated nucleophilic addition-protonation and electrophilic protonation-addition. The first, which begins with nucleophilic attack, takes place under neutral or, more commonly, basic conditions. As the (frequently anionic) nucleophile approaches the electrophilic carbon, the carbon rehybridizes and the electron pair of the tt bond moves over to the oxygen, thereby producing an alkoxide ion. Subsequent protonation, usually from a protic solvent such as water or alcohol, yields the final addition product... 

Note that the new Nu-C bond is made up entirely of the electron pair of the nucleophile. The transformation is reminiscent of an Sn2 reaction. In that process, a leaving group is displaced. Here, an electron pair is moved from a shared position between carbon and oxygen to one solely on the oxygen atom. Additions of strongly basic nucleophiles to carbonyl groups typically follow the nucleophilic addition-protonation pathway. 

Duan SW, An J, Chen JR, Xiao WJ. Facile synthesis of enan-tioenriched Cy-tetrasubstituted a-amino acid derivatives via an asymmetric nucleophilic addition/protonation cascade. Org. Lett. 2011 13 2290-2293. 

Pd(II) compounds coordinate to alkenes to form rr-complexes. Roughly, a decrease in the electron density of alkenes by coordination to electrophilic Pd(II) permits attack by various nucleophiles on the coordinated alkenes. In contrast, electrophilic attack is commonly observed with uncomplexed alkenes. The attack of nucleophiles with concomitant formation of a carbon-palladium r-bond 1 is called the palladation of alkenes. This reaction is similar to the mercuration reaction. However, unlike the mercuration products, which are stable and isolable, the product 1 of the palladation is usually unstable and undergoes rapid decomposition. The palladation reaction is followed by two reactions. The elimination of H—Pd—Cl from 1 to form vinyl compounds 2 is one reaction path, resulting in nucleophilic substitution of the olefinic proton. When the displacement of the Pd in 1 with another nucleophile takes place, the nucleophilic addition of alkenes occurs to give 3. Depending on the reactants and conditions, either nucleophilic substitution of alkenes or nucleophilic addition to alkenes takes place. 

Steric and electronic effects influence the rate of nucleophilic addition to a proton ated carbonyl group m much the same way as they do for the case of a neutral one and protonated aldehydes react faster than protonated ketones... 

Step 2 Nucleophilic addition to the protonated aldehyde or ketone... 

Under conditions of acid catalysis the nucleophilic addition step follows protonation of the carbonyl oxygen Protonation increases the carbocat ion character of a carbonyl group and makes it more electrophilic... 

Nucleophilic addition to the protonated carbonyl to form a tetrahedral intermediate... 

Protonation of the carbonyl oxygen activates the carbonyl group toward nucleophilic addition Addition of an alcohol gives a tetrahedral inter mediate (shown m the box m the preceding equation) which has the capacity to revert to starting materials or to undergo dehydration to yield an ester... 

Step 1 The acid catalyst activates the anhydride toward nucleophilic addition by protonation of the carbonyl oxygen... 

Step 2 Nucleophilic addition of water to protonated form of ester... 

The intermediate formed m the nucleophilic addition step abstracts a proton from the solvent to give the observed product... 

In acid the nitnle is protonated on nitrogen Nucleophilic addition of water yields an imino acid... 

B) Nucleophilic addition at the carbonyl group followed by protonation ... 

Fig. 8.3. Three-dimensional potential energy diagram for addition of a proton and nucleophile to a caibonyl group, (a) Proton transfer complete before nucleophilic addition begins (b) nucleophilic addition complete before proton transfer begins (c) concerted proton transfer and nucleophilic addition.

Because of thetr electron deficient nature, fluoroolefms are often nucleophihcally attacked by alcohols and alkoxides Ethers are commonly produced by these addition and addition-elimination reactions The wide availability of alcohols and fliioroolefins has established the generality of the nucleophilic addition reactions The mechanism of the addition reaction is generally believed to proceed by attack at a vinylic carbon to produce an intermediate fluorocarbanion as the rate-determining slow step The intermediate carbanion may react with a proton source to yield the saturated addition product Alternatively, the intermediate carbanion may, by elimination of P-halogen, lead to an unsaturated ether, often an enol or vinylic ether These addition and addition-elimination reactions have been previously reviewed [1, 2] The intermediate carbanions resulting from nucleophilic attack on fluoroolefins have also been trapped in situ with carbon dioxide, carbonates, and esters of fluorinated acids [3, 4, 5] (equations 1 and 2)... 

Because the pK s of the aldehyde and water are similar, the solution contains significant quantities of both the aldehyde and its enolate. Moreover, their reactivities are complementary. The aldehyde is capable of undergoing nucleophilic addition to its carbonyl group, and the enolate is a nucleophile capable of adding to a carbonyl group. And as shown in Figure 18.4, this is exactly what happens. The product of this step is an alkoxide, which abstracts a proton from the solvent (usually water or ethanol) to yield a (3-hydroxy aldehyde. A compound of this type is known as an aldol because it contains both an aldehyde function and a hydroxyl group (aid + ol = aldol). The reaction is called aldol addition. 

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