Nucleophilic substitution carbonic acid derivatives

These substitution products A and B need not be the final product of the reaction of nucleophiles with carboxyl species. Sometimes they may be formed only as intermediates and continue to react with the nucleophile. Being carbonyl compounds (substitution products A) or carboxylic acid derivatives (substitution products B), they can in principle undergo, another addition or substitution reaction (see above). Thus, carboxylic acid derivatives can react with as many as two equivalents of nucleophiles, and carbonic acid derivatives can react with as many as three. 

R-Y-COCl plays the key role in phosgenation reactions that are of a stepwise nature the major part of these processes is COCl (chlorocarbonyl) transfer to R-Y-H generating chloroformates, carbamoyl chlorides, etc. R-Y-COCl is of limited (low) stability and this is the driving force behind its intermediacy in the synthesis of chlorides and isocyanates under elimination conditions (eliminating CO2 and/or HCl), and also determines the character of a reactive substrate in further nucleophilic substitutions to form symmetrical and unsymmetrical substituted carbonic acid derivatives carbonates, carbamates, ureas) or diaryl ketones. Commonly, chloro-formylation and isocyanate formation are independent of the nature of R. Obviously, the reactivity is very different due to the relative basic/nucleophilic ratio. For example, Ar-Cl cannot be prepared through a chloroformate intermediate nor by direct phosgenation, but the reaction does work well in the aliphatic series. 

Carbonyl complexes also react with non-carbon nucleophiles. The resulting carbonic acid derivatives can serve as starting material for the preparation of bis-heteroatom-substituted carbene complexes [93]. Heterocyclic carbene complexes can be obtained from nucleophiles with a leaving group in -position (Table 2.2). 

In contrast, C=0-containing carboxylic acid and carbonic acid derivatives react with nucleophiles in substitution reactions. The one group or one of the two groups bound through a heteroatom to the carboxyl carbon of these substrates is substituted so that compounds A or B, respectively, are obtained. 

Regarding question (3) the addition of a nucleophile to the C=0 double bond of carboxylic or carbonic acid derivatives would give products of type C or D (Figure 6.1). However, these compounds are without exception thermodynamically less stable than the corresponding substitution products A or B. The reason for this is that the three bonds in the substructure 3(—O—H)—Het of the addition products C and D are together less stable... 

Fig. 6.1. Reactions of nucleophiles with C=0-con-taining carboxylic acid and carbonic acid derivatives. Substitution at the carboxyl carbon instead of addition to the acyl group.

The carboxylic acid derivatives (RC(O)OX) and carbonic acid derivatives (ROC(O)OX) represent two classes of environmental chemicals that hydrolyze through nucleophilic acyl substitution reactions. The general structural features of representative functional groups in these chemical classes are illustrated in Figure 2.6. 

This chapter will revisit the lUPAC nomenclature system for aldehydes, ketones, and carboxylic acids, as well as introduce nomenclature for the four main acid derivatives acid chlorides, anhydrides, esters, and amides. The chapter will show the similarity of a carbonyl and an alkene in that both react with a Br0nsted-Lowry acid or a Lewis acid. The reaction of a carbonyl compound with an acid will generate a resonance stabilized oxocarbenium ion. Ketones and aldehydes react with nucleophiles by what is known as acyl addition to give an alkoxide product, which is converted to an alcohol in a second chemical step. Acid derivatives differ from aldehydes or ketones in that a leaving group is attached to the carbonyl carbon. Acid derivatives react with nucleophiles by what is known as acyl substitution, via a tetrahedral intermediate. 

Nucleophilic reactions of diphosgene highlight its reactivity as a tricoordinated carbonic acid derivative. Its phosgene equivalence can be rationalized in terms of the mechanistic scheme shown below (e.g. route a with a dialkylamine as HNu), whereby a mole of phosgene is released during the nucleophilic substitution. Several examples of route b have also been reported. From the reaction of diphosgene... 

Terminal alkyne anions are popular reagents for the acyl anion synthons (RCHjCO"). If this nucleophile is added to aldehydes or ketones, the triple bond remains. This can be con verted to an alkynemercury(II) complex with mercuric salts and is hydrated with water or acids to form ketones (M.M.T. Khan, 1974). The more substituted carbon atom of the al-kynes is converted preferentially into a carbonyl group. Highly substituted a-hydroxyketones are available by this method (J.A. Katzenellenbogen, 1973). Acetylene itself can react with two molecules of an aldehyde or a ketone (V. jager, 1977). Hydration then leads to 1,4-dihydroxy-2-butanones. The 1,4-diols tend to condense to tetrahydrofuran derivatives in the presence of acids. 

The addition of a nucleophile to a polar C=0 bond is the key step in thre< of the four major carbonyl-group reactions. We saw in Chapter 19 that when. nucleophile adds to an aldehyde or ketone, the initially formed tetrahedra intermediate either can be protonated to yield an alcohol or can eliminate th< carbonyl oxygen, leading to a new C=Nu bond. When a nucleophile adds to carboxylic acid derivative, however, a different reaction course is followed. Tin initially formed tetrahedral intermediate eliminates one of the two substituent originally bonded to the carbonyl carbon, leading to a net nucleophilic acy substitution reaction (Figure 21.1. ... 

Another quite common reaction involving nucleophilic attack at a carbon atom of the ring is the hydrolysis of hexahydro-oxazolo[3,4- ]pyridines and tetrahydro-oxazolo[3,4-tf]pyridin-l-ones. This reaction has been known for years and is best performed under acidic conditions, respectively, producing 2-hydroxymethyl-piperidines or pipe-colic acid derivatives in good yields representative examples are collected in Table 9. Ammoniolysis of tetrahydro-oxazolo[3,4-tf]pyridin-l -ones with amino acid derivatives has also been reported and produces substituted pipecolic acid amides in good yields <2003H(61)259>. 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

Carboxylic acid and its derivatives undergo nucleophilic acyl substitution, where one nucleophile replaces another on the acyl carbon. Nucleophilic acyl substitution can interconvert all carboxylic acid derivatives, and the reaction mechanism varies depending on acidic or basic conditions. Nucleophiles can either be negatively charged anion (Nu ) or neutral (Nu ) molecules. 

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