Conjugate attack

The nitro group (NO2) is extremely electron-withdrawing—about twice as electron-withdrawing as a carbonyl group. This should theoretically make it prefer direct attack rather than conjugate attack but in practice direct attack at N02 is almost unknown. The products from direct attack are very unstable compounds and revert to starting materials easily. You may rely on conjugate addition to nitro-alkenes. 

Wa summarized factors favouring direst versus conjugate attack in Chapter 10, p.240. . ... 

Base catalysis is not required for conjugate addition. If the nucleophile is sufficiently enolized under the reaction conditions then the enol form is perfectly able to attack the unsaturated carbonyl compound. Enols are neutral and thus soft nucleophiles favouring conjugate attack, and p-dicarbonyl compounds are enolized to a significant extent (Chapter 21). Under acidic conditions there can be absolutely no base present but conjugate addition proceeds very efficiently. In this way methyl vinyl ketone (butenone) reacts with the cyclic P-diketone promoted by acetic acid to form a quaternary centre. The yield is excellent and the triketone product is an important intermediate in steroid synthesis as you will see later in this chapter. 

Allyl Halides. In bimolecular substitutions on allyl halides, direct displacement of the halide ion (S 2) almost always occurs, and conjugate attack (Sn2 ) is rare. It is perhaps significant that the few examples of conjugate reaction... 

The palladium forms the usual allyl cation complex and the nitrogen nucleophile attacks the ler hindered end also retaining the conjugation. Attack at the triple bond would give an allene. 

Since the 6+ at the conjugate position is less, the carbon atom is softer, and softer organometallics tend to favor conjugate attack (see Section 9.6). 

A Conjugated System with Two b+ Sites Can Be Attacked at Either Site, Conjugate Addition Is the Thermodynamic Product, Normal Addition Is the Kinetic Product for Hard Nucleophiles, Soft Nucleophiles Prefer Conjugate Attack... 

Because the effect of an electronegative group diminishes with distance, the carbonyl carbon in this system will have the greatest partial plus and therefore will be harder and attract a hard, negatively charged nucleophile best the 1,2 product or normal addition product will be the kinetic product for hard nucleophiles. Soft nucleophiles therefore prefer conjugate attack. Finally, if one site is very sterically hindered, attack at the more open site will dominate. 

That sulfonium ylids can add in a Michael fashion is neatly shown by an intramolecular reaction of the ylid 17. Direct attack would form an awkward 7-membered ring but conjugate attack 17 gives a five-membered ring intermediate with both new C—C bonds necessarily formed cis to the ylid.6 Here is regio- and stereoselectivity. 

ADEPT an antibody-beta-lactamase conjugate attacks a cephalopsorin-anti-cancer drug conjugate to liberate the anti-cancer drug... 

Similarly, the simple lithium enolate 4.143 reacts with cyclohexenone at -78 °C to give the product 4.142 of direct attack, but warming the reaction mixture to room temperature allows this step to revert to the starting materials, and they then form the thermodynamically more stable product 4.144 of conjugate attack.374 /3-Dicarbonyl enolates, commonly used in Michael reactions, usually do not allow the isolation of the product of direct attack, since the first step is even more easily reversible in such cases. 

The thiolate anion (RS /ArS ) does not react with oc,p-unsaturated esters to give or, p-unsaturated thioesters 98 because the equilibrium favors the ester. However, reaction with esters gives the products of conjugate addition 99 exclusively. The relative rate of attack at both the sites can, therefore, not be measured. It is likely that the conjugate attack is kinetically controlled. 

Reactions with Nucleophiles. As an enone tropone is readily susceptible to attack by nucleophiles in Michael-type reactions which might take place at any site in the ring. An early reported example was the formation of 2-aminotropone by reaction with either hydrazine or hydroxyl amine [169]. Reaction olsviously proceeds by conjugate attack (preferred over attack at the carbonyl group) followed by elimination of water or ammonia ... 

Dithiols also react both by conjugate attack and at the carbonyl group [175,176] ... 

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