Carbon-bonded substituents nucleophilic reactions

The previous sections dealt with reactions in which the new carbon-carbon bond is formed by addition of the nucleophile to a carbonyl group. Another important method for alkylation of carbon nucleophiles involves addition to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,(3-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. 

For carbon-carbon bond-formation purposes, S 2 nucleophilic substitutions are frequently used. Simple S 2 nucleophilic substitution reactions are generally slower in aqueous conditions than in aprotic organic solvents. This has been attributed to the solvation of nucleophiles in water. As previously mentioned in Section 5.2, Breslow and co-workers have found that cosolvents such as ethanol increase the solubility of hydrophobic molecules in water and provide interesting results for nucleophilic substitutions (Scheme 6.1). In alkylations of phenoxide ions by benzylic chlorides, S/y2 substitutions can occur both at the phenoxide oxygen and at the ortho and para positions of the ring. In fact, carbon alkylation occurs in water but not in nonpolar organic solvents and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para). The effects of phenol substituents and of cosolvents on the rates of the competing alkylation processes... 

Compound 874, as a representative of derivatives with an electron-withdrawing substituent at C-[1 of the vinyl group, is easily prepared by elimination of one benzotriazole from 2,2-/fo(benzotriazol-l-yl)ethyl methyl ketone 873. The stereoselective elimination catalyzed by NaOH gives exclusively the (E) isomer of derivative 874. Addition of nucleophiles to the double bond of vinyl ketone 874 followed by elimination of benzotriazole leads to a,P unsaturated ketones 875. Amines used as nucleophiles do not need any catalysis, but reactions with carbon and sulfur nucleophiles require addition of a base. The total effect is nucleophilic substitution of the benzotriazolyl group at the i-carbon of orji-iinsaturatcd ketone (Scheme 142) <1996SC3773>. 

Sn2 and SNAr Reactions In these reactions the metal atom attacks aliphatic or aromatic carbon bonded to X, respectively. A stronger nucleophilic metal as well as a better leaving group X (I>Br>Cl>F) facilitates, whereas steric hindrance in R slows these types of oxidative addition [193, 194]. SNAr reactions are favored by electron-withdrawing substituents Y in the case of the substrates 4-YQH4X [2], Sn2 [27, 29, 89, 117, 180, 181] and SNAr [31, 33, 62-67, 95, 100, 107-109] mechanisms have been suggested frequently for zerovalent d10 complexes such as [L M] (M = Ni, Pd, Pt L=tertiary phosphine =2,3,4). For example ... 

The earlier transition states, found when a more electron-donating substituent is added to the nucleophile, may be found because a better nucleophile would not have to come as close to the alpha carbon to distort the Ca— N+ bond and cause reaction. 

The reactions described in this chapter include some of the most useful synthetic methods for carbon-carbon bond formation the aldol and Claisen condensations, the Robinson annulation, and the Wittig reaction and related olefination methods. All of these reactions begin by the addition of a carbon nucleophile to a carbonyl group. The product which is isolated depends on the nature of the substituent (X) on the carbon nucleophile, the substituents (A and B) on the carbonyl group, and the ways in which A, B, and X interact to control the reaction pathways available to the addition intermediate. 

Classification of carbene complexes as Fischer or Schrock perhaps focuses too much on their differences and too little on their similarities. Both contain a metal-carbon bond of order greater than one. Whether the carbene carbon tends to seek or provide electrons will depend on the extent of it bonding involving the metal and the carbon substituents. Some carbene complexes lie between the Fischer/Schrock extremes, behaving in some reactions as nucleophiles and in others as electrophiles.69... 

The high electron density in the double bond system of ethylenes makes nucleophilic attack unfavorable unless the system is substituted with one or more electron withdrawing groups such as -N02, -CN, -COR. When these substituents are present, attack by alcohols or alkoxide ions occurs at the beta-carbon predominantly. For example, researchers have found (12) that sodium methoxide or sodium ethoxide added rapidly at room temperature to beta-nitrostyrene leads to the alkoxide formation of the derivative (Reaction VIII). This reaction is generally not only for arylnitroalkenes (13) but also for other activated double bonds (14). Another example of alcohol addition to an activated double bond includes the reaction of alcohols with acrylonitrile to produce a cyano-ethylated ether (14A). 

The classical Mannich aminomethylation is one of the most important ionic carbon-carbon bond forming reactions in organic chemistry [35]. However, only substituents with electron-withdrawing groups are suitable for the ionic addition. Electron-donating groups directly bonded to the carbon-centered radical favor nucleophilic radical addition to methylene-iminium salts. Thus, the radical-type Mannich reaction provides products which are complementary to those obtained with the classical ionic reaction. 

The same authors chose another very reactive nucleophilic function, the silyl enol ether group, which upon reaction with living cationic chain ends of poly(vinyl ether)s, also leads to a carbon-carbon bond with formation of a ketone (Scheme 4). Model reactions of living poly(IBVE) with various monofunctional silyl enol ethers [47] showed that the a-substituent R should have electron-donating properties in order to increase the electron density on the double bond. 

Since its discovery by Tsuji [15,16] and catalytic expansion by Hata [17] and Atkins [18], allylic substitution has become the most popular palladium-catalyzed method for carbon-carbon bond formation along with crosscoupling reactions. However, the first report using NHC in this transformation only appeared recently [19]. An imidazolium salt with a bulky substituent on the nitrogen atoms, IPr HC1, was found to be a suitable ligand for allylic substitution with soft nucleophiles (Scheme 2). Pd2(dba)3 as palladium source and Cs2C03 as base completed the catalyst system. 

The key idea of the Zimmerman-Traxler model is that aldol additions proceed via six-membered ring transition state structures. In these transition states, the metal (a magnesium cation in the case of the Ivanov reaction) coordinates both to the enolate oxygen and to the O atom of the carbonyl compound. By way of this coordination, the metal ion guides the approach of the electrophilic carbonyl carbon to the nucleophilic enolate carbon. The approach of the carbonyl and enolate carbons occurs in a transition state structure with chair conformation. C—C bond formation is fastest in the transition state with the maximum number of quasi-equatorially oriented and therefore sterically unhindered substituents. 

The Michael reaction involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic partners are typically a,fi-unsaturated ketones, esters or nitriles, but other electron-withdrawing substituents can be used to activate the carbon—carbon double bond to nucleophilic attack. A tandem aldol-Michael reaction has been recently described. Wachter-Jurcsak and coworkers66 reported that the reactions involving 2-pyridinecarboxaldehyde, 71, and 2-quinolinecarboxaldehyde with the enolates of acetophenone, 70, afforded the unexpected symmetric l,5-diphenyl-3-(2-heteroaryl)-1,5-pentanediones (Scheme 24). 

---