Nucleophilic addition-elimination mechanism

A number of compounds of the general type H2NZ react with aldehydes and ketones m a manner analogous to that of primary amines The carbonyl group (C=0) IS converted to C=NZ and a molecule of water is formed Table 17 4 presents exam pies of some of these reactions The mechanism by which each proceeds is similar to the nucleophilic addition-elimination mechanism described for the reaction of primary amines with aldehydes and ketones... 

It has been suggested that the elusive zwitterionic state [75], or a novel nucleophilic addition/elimination mechanism at the central carbon of the exocyclic bridge [79], or solvent-solute H-bonding interactions [76, 80] might play a role in modulating cis-trans interconversion. Cis-trans isomerization gives rise also to a remarkable intrinsic photochromism of HBI, as it can be easily and reversibly induced upon light absorption [74—76, 79, 80]. 

A nucleophilic mechanism can be applied in reductions with complex hydrides of highly fluori-nated aliphatic and alicyclic fluoroalkenes with electron-deficient C = C bonds the hydride anion adds as a strong nucleophilic agent to the more electrophilic carbon atom the intermediate anion can then lose a fluoride ion either from the original C = C bond, or from the allylic position finishing an SN2 displacement of the fluorine. Thus, the reductions of vinylic C-F bonds with hydrides proceed by a nucleophilic addition-elimination mechanism. Displacement of fluorine in highly fluorinated aromatic compounds proceeds by the same mechanism ... 

Vinylic fluorine in lithium 2,3,3-trifluoroprop-2-enoate is substituted with hydride ion by a nucleophilic addition-elimination mechanism using lithium aluminum hydride at low temperatures.113... 

Although the two competing intermediates, the hypothetical ketyl-aryl radical pair (4) and the oxaspirooctadienyllithium (3), are not the rate-determining transition states, they should lie at almost the same energetic level. The rearrangement is in accord with the intramolecular nucleophilic addition/elimination mechanism rather than with homolytic cleavage/recombination. 

Kinetic Evidence against Nucleophilic Addition-Elimination Mechanism.339... 

KINETIC EVIDENCE AGAINST NUCLEOPHILIC ADDITION-ELIMINATION MECHANISM... 

Kinetic studies were carried out by online IR. First-order kinetics in the free acid 3 and zero-order kinetics in BocNHOBoc were clearly observed. The yield and rate were almost identical when 1 or 2 equiv of BocNHOBoc were used. The k bs values (Table 21.2, entries 1 to 2) obtained by online IR are very close to those measured for the self-decomposition of 3, in which the ratedetermining step is likely the formation of a-oxoketene 2. To conclude, the k values and the observed hrst-order kinetics in HA do not support the nucleophilic addition-elimination mechanism and are consistent with a pathway via the oxoketene 8. 

The hydrolysis of Fischer carbene complexes such as 11,13,42,87 and 112 has been discussed in the section Hydroxide ion and water as nucleophiles and proceeds by a standard nucleophilic addition-elimination mechanism (equation 74). On the other hand, carbene complexes with ionizable a-carbons are hydrolyzed by a different mechanism which involves the deprotonated carbene complex as the key intermediate. This conclusion is based on a detailed kinetic investigation of the hydrolysis of 66, 68, 144 and 8 in 50% MeCN-50%... 

Substrate binding and activation are followed by attack of the carboxylate side chain of Asp-145 at the benzoyl C-4 atom to give an enzyme-stabilized Meisenheimer intermediate (EMc) (Figure 8). Indeed, a site-directed mutant in which Asp-145 has been replaced by an alanine is catalytically inactive." Ketonization of the EMc results in rearomatization of the benzoyl ring and expulsion of the chloride. This nucleophilic addition-elimination mechanism (SNAr-type reaction) results in a second covalent (aryl-enzyme) intermediate, which is subsequently hydrolyzed by a water molecule that is activated by His-90 to give the free enzyme and the product. The existence of a covalent aryl-enzyme intermediate has been inferred from 0-labeling studies (similar to those described for haloalkane and haloalcohol dehalogenase) and from the direct measurement of the aryl-enzyme... 

The overall process, therefore, is acyl substitution by a nucleophilic addition-elimination mechanism. 

The reactions of carboxylic acids and their derivatives are summarized here. Many (but not all) of the reactions in this summary are acyl substitution reactions (they are principally the reactions referenced to Sections 17.5 and beyond). As you use this summary, you will find it helpful to also review Section 17.4, which presents the general nucleophilic addition-elimination mechanism for acyl substitution. It is instructive to relate aspects of the specific acyl substitution reactions below to this general mechanism. In some cases proton transfer steps are also involved, such as to make a leaving group more suitable by prior protonation or to transfer a proton to a stronger base at some point in a reaction, but in all acyl substitution the essential nucleophilic addition-elimination steps are identifiable. 

We have now discussed Fischer esterification (formation of an ester in an acidic solution of an alcohol) and fhe hydrolysis of an ester in acidic water. When we discussed Fischer esterification, we pointed out that it is an equilibrium reaction. Ester hydrolysis in aqueous acid is also an equilibrium reaction. The two reactions proceed via the same nucleophilic addition/elimination mechanism, except that they are the reverse of each other. As first introduced in Section 10.6, the prmdple of microscopic reversibility states that for any reversible reaction, the sequence of intermediates and transition states must be the same but in reverse order for the backward versus forward reaction. In general, the reverse of protonation (Add a proton) is deprotonation (Take a proton away). The reverse of nucleophilic affack (Make a bond between a nucleophile and an electrophile) is leaving group departure (Break a bond to give stable molecules or ions). 

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