Carboxylates as nucleophiles

In the initial step, the first BOC-protected amino acid is bound to the polymer, e.g. polystyrene in which a proportion of the phenyl rings have chloromethyl substitution. Attachment to these residues is through the carboxyl via an ester linkage. This involves a simple nucleophilic substitution reaction, with the carboxylate as nucleophile and chloride as leaving group (see Section 6.3.2). After each stage, the insoluble polymer-product combination is washed free of impurities. 

Metal carboxyiates have been considered as nucleophilic agents capable of removing aHyUc chlorine and thereby affording stabilization (143). Typical PVC stabilizers, eg, tin, lead, or cadmium esters, actually promote the degradation of VDC polymers. The metal cations in these compounds are much too acidic to be used with VDC polymers. An effective carboxylate stabilizer must contain a metal cation sufftcientiy acidic to interact with aHyUc chlorine and to facihtate its displacement by the carboxylate anion, but at the same time not acidic enough to strip chlorine from the polymer main chain (144). 

Carboxylate anions can also serve as nucleophilic catalysts. In this case, an anhydride is the reactive intermediate ... 

Carboxylic acids have also been investigated as nucleophiles in the ring-opening of aziridine-2-carboxylates [103]. Solvation of compounds 129 (Scheme 3.46) in acetic acid, for example, gave 130a and 130b in 83% and 89% yields, respectively. 

Other carbanionic groups, such as acetylide ions, and ions derived from a-methylpyridines have also been used as nucleophiles. A particularly useful nucleophile is the methylsulfinyl carbanion (CH3SOCHJ), the conjugate base of DMSO, since the P-keto sulfoxide produced can easily be reduced to a methyl ketone (p. 549). The methylsulfonyl carbanion (CH3SO2CH2 ), the conjugate base of dimethyl sulfone, behaves similarly, and the product can be similarly reduced. Certain carboxylic esters, acyl halides, and DMF acylate 1,3-dithianes (see 10-10. )2008 Qxj(jatjye hydrolysis with NBS or NCS, a-keto aldehydes or a-... 

The imidazolide group at the amino end of an amino acid is as reactive toward nucleophiles as the imidazolide group at the carboxylic end of an amino acid. If an N-protected amino acid is selected as nucleophile, this method can also be used for peptide synthesis. The amino-activated amino acids, for example N-( 1 -imidazolylcarbonyl)-amino acid esters, are prepared from a-isocyanatocarboxylic acids and imidazole. 

Besides fragmentation or rearrangement, the carboxylic acid anions, formed by an enzymatic hydrolysis, can also act as nucleophiles. Kuhn and Tamm used the asymmetric hydrolysis of meso-epoxy diester 8-28 with PLE to synthesize y-lactone... 

A different dimerization takes place in formic acid (33. 34). Unlike other carboxylic acids which behave as nucleophiles, formic acid behaves as a reductant and the dimerization proceeds with partial reduction. By carrying out the reaction in a mixture of formic acid and triethylamine at 59°C using Pd(OAc)2, 1,6-octadiene (24) was obtained. 

Introduction 877 Alcohols as Nucleophiles 881 Allenyl Ketones 889 Allenic Carboxylic Acids 895... 

According to Ganem and Small [5], the reaction mechanism is an acylation at the ether oxygen followed by a dissociation step, either of an SaU or Sat2 nature. With carboxylate as the nucleophile, both the Sjvl and S v2 routes are feasible. Regardless of the true mechanism, the net effect of this ether-to-diester reaction is an insertion of esters to ether bonds. 

Jacobsen et al. [48], in 1997 for the first time demonstrated KR of racemic terminal epoxides with water as nucleophile for the production of optically pure epoxides and corresponding 1,2-diols. Since then, various other nucleophiles viz., carboxylic acids, phenols, thiols, amines, carbamates and indols were used in KR to produce optically pure epoxides with concomitant production of corresponding enantioenriched l,2-bifimctional moieties [49-52]. 

Oxygen and sulfur as nucleophiles esters and carboxylic acids... 

OXYGEN AND SULFUR AS NUCLEOPHILES ESTERS AND CARBOXYLIC ACIDS... 

All carboxylic acid derivatives are hydrolysed to carboxylic acids by the action of water as nucleophile. Acyl halides and anhydrides of low molecular weight are hydrolysed quite vigorously. Esters and amides react much more slowly, and hydrolysis normally requires acid or base catalysis. This is nicely... 

The a-hydrogens of carboxylic acid derivatives show enhanced acidity, as do those of aldehydes and ketones, and for the same reasons, that the carbonyl group stabilizes the conjugate base. Thus, we can generate enolate anions from carboxylic acid derivatives and use these as nucleophiles in much the same way as we have already seen with enolate anions from aldehydes and ketones. 

Alkylation of the a-position of suitable carboxylic acid derivatives may be achieved using the enolate anion as nucleophile in a typical Sn2 reaction (compare Section 10.2). In the example shown, the... 

To participate in this sort of reaction, the carboxylic acid derivative acting as nucleophile must have a-hydrogens in order to generate an enolate anion. In practice, esters are most commonly employed in Claisen-type reactions. 

The fatty acid is initially converted into an acyl-AMP derivative by attack of the carboxylate as a nucleophile onto the P=0 system of ATP, with loss of diphosphate as a leaving group. This reaction is far from favourable, and the equilibrium is disturbed by subsequent pyrophosphatase-catalysed hydrolysis of diphosphate into two molecules of phosphate. 

The amide derived from the carboxylic acid in Ugi adducts is in most cases tertiary, and therefore it cannot serve as nucleophilic partner in post-condensation transformations, unless a post-Ugi rearrangement converts it into a free amine [52, 54]. An exception is represented by Ugi adducts derived from ammonia, which give rise to two secondary amides, each of them potentially involved, as nucleophile, in nucleophilic substitution processes. Four competitive pathways are in principle possible (N- or 0-alkylations of the two amides), and the reaction is mainly driven by the stability of the formed rings. In the example shown in Fig. 12, 0-alkylation of the carboxylic-derived amide is favoured as it generates a 5-membered ring (oxazoline 62), while the alternative cyclization modes would have formed 3- or 4-membered rings [49]. When R C02H is phthalic acid, however, acylaziridines are formed instead via Walkylation [49]. In both cases, the intramolecular 8 2 reactions takes place directly under the Ugi conditions. 

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