Nucleophilicity carbonyl halides

Deviating from the route via nucleophilic attack of the carbanion at the carbon atom of a CO ligand and then reaction of the acylmetallate with an electrophile are those methods which involve (a) addition of the carbanion to the carbon atom of a carbyne ligand, (b) displacement of halides from transition-metal carbonyl halides by cyclohepta-trienyllithium, or derivatives thereof, followed by hydride abstraction or (c) substitution of a coordinated solvent from a metal-carbonyl complex (see also reaction of LiR with carbene complexes). 

In the Sections above, various aspects of the electronic structure of the carbonyl halides have been discussed in some detail, and it is now appropriate to consider what insight this knowledge yields concerning their chemical reactivity. In particular, their reactivity towards nucleophilic and electrophilic substitutions will be examined. 

The major classes of carbonyl compounds include aldehydes, ketones, carboxamides, esters, carboxylic acids and anhydrides, and carbonyl halides (acyl halides). These groups differ in the identity of the substituent X on the carbonyl group. At this point we concentrate on these examples, but a number of other carbonyl derivatives have important roles in synthetic and/or biological reactions. These other compounds include acyl cyanides, acyl azides, A-acylimidazoles, 0-aryl esters, and thioesters. The carbonyl compounds are arranged below in the order of the increasing reactivity toward nucleophilic addition. 

Elimination of hydrogen halides, particularly in the presence of base, is also a common reaction (equation 54). The actual mechanism of these reactions could involve nucleophilic displacement of halide by the metal carbonyl halide that is formed in situ from the hydride (equations 55 and 56). 

In Scheme 1.2, all of the types of carbonylations that are discussed in the book are depicted. Alcohols, amines, ethers, carboxylic acids and halides can be converted to acids, amides, esters, ketones, alkynones, alkenones, anhydrides and acid halides with the assistance of transition metal catalysts in the presence of a CO source. The CO sources used can be carbon monoxide gas, Mo(CO)6, Co(CO>6, formic acid, aldehyde, etc. If the starting material is alcohols or amines, some additives for activation are needed, such as BuONO, TsCl, AcCl. If the substrate is (Hetero)ArH, additional oxidants will be necessary this is a so-caUed oxidative carbonylation. If an unsaturated compound is to be carbonylated, a nucleophile NuH that carries an acidic hydrogen has to be present. In the case of insertion reactions, this is not necessary. 

A disadvantage of the synthesis of metal-alkyl complexes by transmetallation is the potential for nucleophilic attack to occur at ancillary ligands. Carbonyl ligands are particularly vulnerable to nucleophilic attack, as shown in Equation 3.4, and described in more detail in Chapter 11. However, the extent to which this process competes with transmetallation depends on the electronic property of the metal. Thus, some carbonyl halides can be converted into alkyl carbonyl complexes (Equation 3.5). In addition, electron transfer from electron-rich carbon nucleophiles can limit the yields of transmetallation processes. 

Mixed Ligand Carbonyls.—General. Solvent and structural effects on reactivities of metal carbonyl halides towards carbon monoxide replacement have been probed for manganese, iron, and ruthenium compounds. The compounds were MnX(CO>5, where X == Br or I, RuX(CO)2(/i -C6H6), where X = Cl or Br, and FeX(CO)2(/i -C3H5), where X = Br or I. The displacing nucleophiles were triphenylphosphine or triphenyl phosphite the solvents were n-octane, xylene, di-n-butyl ether, or nitrobenzene. Kinetic parameters for some of these reactions, with some earlier values for related systems for comparison, are listed in Table 1. The main conclusion... 

Alkyl and 2-Alkenyl Halides or Sulfonates Ring Opening of Cyclic Amines and Ethers Addition onto Carbon-Carbon Multiple Bonds Addition onto Heteroconjugated Multiple Bonds Nucleophilic Substitution of 1-Alkenyl Halides Nucleophilic Addition onto Arenes and Hetarenes Substitution of Halo-, Alkoxy-, and Metalloarenes or -hetarenes Addition onto Nonaromatic Carbon-Nitrogen Multiple Bonds Addition onto Carbonyl Compounds... 

Most syntheses of nitrogen heterocycles involve substitution and/or condensation reactions of nitrogen nucleophiles with difunctional halides or carbonyl compounds. Common nitrogen reagents are ... 

Formation of carboxylic acids ami their derivatives. Aryl and alkenyl halides undergo Pd-catalyzed carbonylation under mild conditions, offering useful synthetic methods for carbonyl compounds. The facile CO insertion into aryl- or alkenylpalladium complexes, followed by the nucleophilic attack of alcohol or water affords esters or carboxylic acids. Aromatic and a,/ -unsaturated carboxylic acids or esters are prepared by the carbonylation of aryl and alkenyl halides in water or alcohols[30l-305]. 

Formation of ketones. Ketones can be prepared by the carbonylation of halides and pseudo-halides in the presence of various organometallic compounds of Zn, B, Al, Sn, Si, and Hg, and other carbon nucleophiles, which attack acylpalladium intermediates (transmetallation and reductive elimination). 

The behavior of such activated halides as alkylating agents under Friedel-Crafts conditions expands the scope of the synthesis. Aluminum chloride enhances the electrophilic character of the a,/S-unsaturated carbonyl system and permits the nucleophilic attachment of the aromatic addendum (Y ) to the carbon bearing the positive charge, with displacement of halogen [Eq. (5)]. Thus,... 

In the presence of strong bases, carbonyl compounds form enolate ions, which may be employed as nucleophilic reagents to attack alkyl halides or other suitably electron-deficient substrates giving carbon-carbon bonds. (The aldol and Claisen condensations... 

I Primary alkyl halides S 2 substitution occurs if a good nucleophile is used, 2 elimination occurs if a strong base is used, and ElcB elimination occurs if the leaving group is two carbons away from a carbonyl group. 

The reduction of carbonyl compounds by reaction with hydride reagents (H -) and the Grignard addition by reaction with organomagnesium halides (R - +MgBr) are examples of nucleophilic carbonyl addition reactions. What analogous product do you think might result from reaction of cyanide ion with a ketone ... 

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

Conversion of Acid Halides into Acids Hydrolysis Acid chlorides react with water to yield carboxylic acids. This hydrolysis reaction is a typical nucleophilic acyl substitution process and is initiated by attack of water on the acid chloride carbonyl group. The tetrahedral intermediate undergoes elimination of Cl and loss of H+ fo give the product carboxylic acid plus HC1. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Pyridones can also be converted to 2-chloropyridines by exchanging the carbonyl functionality using phosphoroxychloride (POCI3) [72]. A combination of N-halosuccinimides and triphenylphosphine has also been applied to introduce halogens in this position [73]. The carbonyl functionality in 2-pyridones makes these systems reactive towards nucleophiles as well, which add in 1,4-reactions with displacement of halides [74]. The use of transition metal mediated couplings like Heck, and Suzuki have also been successfully applied on halogenated 2-pyridones (d. Scheme 10) [36,75]. 

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