Nucleophilic addition reaction

Biochemistry is carbonyl chemistiy. Almost all metabolic pathways used by living organisms involve one or more of the four fundamental carbonvl-group reactions we ve seen in Chapters 19 through 23. The digestion and metabolic breakdown of all the major classes of food molecules—fats, carbohydrates, and proteins—take place by nucleophilic addition reactions, nucleophilic acyl substitutions, a substitutions, and carbonyl condensations. Similarly, hormones and other crucial biological molecules are built up from smaller precursors by these same carbonyl-group reactions. 

Enantiomeric purity, palladacycle applications, 8, 295 Enantioselective addition reactions, nucleophiles to allylic... 

The compounds that we are now calling dienophiles were the stars of Chapters 10, 23, and 29 where we called them Michael acceptors as they were the electrophilic partners in conjugate addition reactions. Nucleophiles always add to the (3 carbon atoms of these alkenes because the product is then a stable enolate. Ordinary alkenes do not react with nucleophiles. 

Acid - base reactions Substitution reactions Elimination reactions Addition reactions Nucleophilic acyl addition Oxidation reactions Reduction reactions... 

In 1997 Katritzky reported that the Michael addition of a-benzotriazole nitrile 12 to a,p-unsaturated ketones 11 in the presence of a secondary amine generated 2-aminopyridines, IS. This innovative [3+3] strategy provides an alternative to the typical method of preparing 2-aminopyridines by reacting 2-halopyridines with aliphatic amines. Following the initial Michael addition reaction, nucleophilic attack by the secondary amine on the nitrile moiety initiates the cyclization. This is followed by loss of benzotriazole and water to generate the 2-aminopyridine 13. 

Elimination of H and Cl produces a very high energy intermediate called benzyne. This intermediate does not survive long because it is quickly attacked by the nucleophile, producing an addition reaction. Nucleophilic attack can take place at (a) the position of the isotopic label or (b) the other end of the triple bond. 

Several types of Pd-catalyzed or -promoted reactions of conjugated dienes via TT-allylpalladium complexes are known. The Pd(II)-promoted oxidative difunctionalization reactions of conjugated dienes with various nucleophiles is treated in Chapter 3, Section 4, and Pd(0)-catalyzed addition reactions of conjugated dienes to aryl and alkenyl halides in this chapter. Section 1.1.1. Other Pd(0)-catalyzed reactions of conjugated dienes are treated in this section. 

Like butadiene, allene undergoes dimerization and addition of nucleophiles to give 1-substituted 3-methyl-2-methylene-3-butenyl compounds. Dimerization-hydration of allene is catalyzed by Pd(0) in the presence of CO2 to give 3-methyl-2-methylene-3-buten-l-ol (1). An addition reaction with. MleOH proceeds without CO2 to give 2-methyl-4-methoxy-3-inethylene-1-butene (2)[1]. Similarly, piperidine reacts with allene to give the dimeric amine 3, and the reaction of malonate affords 4 in good yields. Pd(0) coordinated by maleic anhydride (MA) IS used as a catalyst[2]. 

The most important chemical property of the carbonyl group is its tendency to undergo nucleophilic addition reactions of the type represented m the general equation... 

As with other reversible nucleophilic addition reactions the equilibria for aldol additions are less favorable for ketones than for aldehydes For example only 2% of the aldol addition product of acetone is present at equilibrium... 

With certain other nucleophiles addition takes place at the carbon-carbon double bond rather than at the carbonyl group Such reactions proceed via enol intermediates and are described as conjugate addition ox 1 4 addition reactions... 

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a p unsaturated ketones The most common types of carbanions used are enolate 10ns derived from p diketones These enolates are weak bases (Section 18 6) and react with a p unsaturated ketones by conjugate addition... 

In addition to being more basic than arylammes alkylammes are also more nucleophilic All the reactions m Table 22 4 take place faster with alkylammes than with arylammes The sections that follow introduce some additional reactions of amines In all cases our understanding of how these reactions take place starts with a consideration of the role of the unshared electron pair of nitrogen... 

Chemical Properties. The chemistry of ketenes is dominated by the strongly electrophilic j/)-hybridi2ed carbon atom and alow energy lowest unoccupied molecular orbital (LUMO). Therefore, ketenes are especially prone to nucleophilic attack at Cl and to [2 + 2] cycloadditions. Less frequent reactions are the so-called ketene iasertion, a special case of addition to substances with strongly polarized or polarizable single bonds (37), and the addition of electrophiles at C2. For a review of addition reactions of ketenes see Reference 8. 

Nucleophilic Addition Reactions. Many nucleophiles, including amines, mercaptans, and alcohols, undergo 1,4-conjugate addition to the double bond of methacrylates (12—14). 

Rifamycin S also undergoes conjugate addition reactions to the quinone ring by a variety of nucleophiles including ammonia, primary and secondary amines, mercaptans, carbanions, and enamines giving the C-3 substituted derivatives (38) of rifamycin SV (117,120,121). Many of the derivatives show excellent antibacterial properties (109,118,122,123). The 3-cycHc amino derivatives of rifamycin SV also inhibit the polymerase of RNA tumor vimses (123,124). 

Addition Reactions. The addition of nucleophiles to quinones is often an acid-catalyzed, Michael-type reductive process (7,43,44). The addition of benzenethiol to 1,4-benzoquinone (2) was studied by A. Michael for a better understanding of valence in organic chemistry (45). The presence of the reduced product thiophenyUiydroquinone (52), the cross-oxidation product 2-thiophenyl-1,4-benzoquinone [18232-03-6] (53), and multiple-addition products such as 2,5-(bis(thiophenyl)-l,4-benzoquinone [17058-53-6] (54) and 2,6-bis(thiophenyl)-l,4-benzoquinone [121194-11-4] (55), is typical ofmany such transformations. 

The NOBS system undergoes an additional reaction that forms a diacyl peroxide as a result of the nucleophilic attack of the peracid anion on the NOBS precursor as shown in equation 21. This undesirable side reaction can be minimized by the use of an excess molar quantity of hydrogen peroxide (91,96) or by the use of shorter dialkyl chain acid derivatives. However, the use of these acid derivatives also appears to result in less efficient bleaching. The dependence of the acid group on the side product formation is apparentiy the result of the proximity of the newly formed peracid to unreacted NOBS in the micellar environment (91). A variety of other peracid precursor stmctures can be found (97—118). 

Micha.elAdditions. The reaction of a bismaleimide with a functional nucleophile (diamine, bisthiol, etc) via the Michael addition reaction converts a BMI building block into a polymer. The non stoichiometric reaction of an aromatic diamine with a bismaleimide was used by Rhc )ne Poulenc to synthesize polyaminobismaleimides as shown in Figure 6 (31). 

The Michael addition of nucleophiles to the carbon—carbon double bond of maleimide has been exploited ia the synthesis of a variety of linear polymers through reaction of bismaleimide with bisthiols (39). This method has been used to synthesize ethynyl-terminated imidothioether from the reaction of 4,4 -dimercaptodiphenyl ether [17527-79-6] and A/-(3-ethynylphenyl)maleimide (40). The chemical stmcture of this Michael addition imide thermoset is as follows ... 

Etherification. The accessible, available hydroxyl groups on the 2, 3, and 6 positions of the anhydroglucose residue are quite reactive (40) and provide sites for much of the current modification of cotton ceUulose to impart special or value-added properties. The two most common classes into which modifications fall include etherification and esterification of the cotton ceUulose hydroxyls as weU as addition reactions with certain unsaturated compounds to produce ceUulose ethers (see Cellulose, ethers). One large class of ceUulose-reactive dyestuffs in commercial use attaches to the ceUulose through an alkaH-catalyzed etherification by nucleophilic attack of the chlorotriazine moiety of the dyestuff ... 

Sinulatly, nucleophilic reagents are suitable for addition reactions only if they are not so strongly basic as to produce the cyanamide anion in large amounts. In such cases, dicyandiamide is produced or a cyanamide salt is obtained. Ai,Ai-Disubstituted cyanamides do not ionize, of course, and react easily with strongly basic nucleophiles. 

The action of sulfur nucleophiles like sodium bisulfite and thiophenols causes even pteridines that are unreactive towards water or alcohols to undergo covalent addition reactions. Thus, pteridin-7-one smoothly adds the named S-nucleophiles in a 1 1 ratio to C-6 (65JCS6930). Similarly, pteridin-4-one (73) yields adducts (74) in a 2 1 ratio at C-6 and C-7 exclusively (equation 14), as do 4-aminopteridine and lumazine with sodium bisulfite. Xanthopterin forms a 7,8-adduct and 7,8-dihydropterin can easily be converted to sodium 5,6,7,8-tetrahydropterin-6-sulfonate (66JCS(C)285), which leads to pterin-6-sulfonic acid on oxidation (59HCA1854). 

The use of carbon nucleophiles in Michael-type addition reactions with pteridine and its derivatives leads to a quite complicated and divergent pattern. These reactions are strongly dependent on the nature of the carbon nucleophile and can be divided into various categories. 

The addition of nucleophiles to double and triple bond systems is often a convenient way of effecting an intramolecular ring closure. Addition to cyano groups has received considerable attention, as in addition to ring formation it provides a convenient method for the introduction of an amino group. Reaction of methyl Af-cyanodithiocarbimidate with Af-methylaminoacetonitrile resulted in displacement of methanethiol and formation of (314). Sodium ethoxide treatment in DMF converted (314) into a 4-amino-5-cyanoimidazole... 

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