Chemical synthesis carboxylic acid derivatives

Acid chlorides are noxious, irritating chemicals and must be handled with great care. They are slightly polar and boil at approximately the same temperature as the corresponding aldehyde or ketone of comparable molecular weight. They react violently with water and therefore cannot be dissolved in that solvent. Acid chlorides have little commercial value other than their utility in the synthesis of esters and amides, two of the other carboxylic acid derivatives. 

This Learning Group Problem focuses on the chemical synthesis of small proteins, called peptides. The essence of peptide or protein synthesis is formation of the amide functional group by reaction of an activated carboxylic acid derivative with an amine. 

Carbonylation reaction offers the production of more functionalized products starting from readily available feedstocks. The process represents industrial core technologies for converting various bulk chemicals such as olefins to aldehydes, alcohols and carboxylic acid derivatives. Advancement in the synthesis and knowledge of various metal carbonyls give access to various new kinds of carbonylation reactions and help in functionalization of various substrates which are otherwise difficult to synthesize. Various types of carbonylation reactions are summarized in Table 10.2. 

Most physiologically active compounds owe their biological properties to the presence of heteroatoms, mainly in the form of heterocydes. A majority of the known natural products are heterocyclic. It is therefore not surprising that more than half the published chemical literature deals with such compounds—then-synthesis, isolation, and interconversions. Indeed, we have already encountered many examples—the cyclic ethers (Section 9-6), acetals (Sections 17-8, 23-4, and 24-8), carboxylic acid derivatives (Chapters 19 and 20), and amines (Chapter 21). The bases in DNA, whose sequence stores hereditary information, are heterocydes (Section 26-9) so are many vitamins, such as Bi (thiamine. Real Life 23-2), B2 (riboflavin. Real Life 25-3), Bg (pyridoxine), the spectacularly complex B12, and vitamins C and E (Section 22-9). The structures of vitamins Bg and B12, as well as additional examples of heterocyclic systems and their varied uses, are depicted here. 

In 2007, Milstein reported an approach for the transition metal catalysed intermolecular formation of amides from alcohols and amines in the absence of a hydrogen acceptor (Scheme 12.19). In contrast with conventional amide synthesis from activated carboxylic acid derivatives which produces chemical waste, this environmentally benign approach produces hydrogen gas as the only byproduct. The catalyst used for this reaction is a dearomatised Ru(PNN)pincer complex which serves as a bifunctional catalyst. The ligands, as well as the metal centre, play a role in bond making or bond breaking steps of the catalytic cycle. 

In the early 1930 s, when the prime research aim was the commercial synthesis of the sex hormones (whose structures had just been elucidated), the principal raw material available was cholesterol extracted from the spinal cord or brain of cattle or from sheep wool grease. This sterol (as its 3-acetate 5,6-dibromide) was subjected to a rather drastic chromic acid oxidation, which produced a variety of acidic, ketonic and hydroxylated products derived mainly by attack on the alkyl side-chain. The principal ketonic material, 3j -hydroxyandrost-5-en-17-one, was obtained in yields of only about 7% another useful ketone, 3 -hydroxypregn-5-en-20-one (pregnenolone) was obtained in much lower yield. The chief acidic product was 3j -hydroxy-androst-5-ene-17j -carboxylic acid. All three of these materials were then further converted by various chemical transformations into steroid hormones and synthetic analogs ... 

In an attempt to identify new, biocompatible diphenols for the synthesis of polyiminocarbonates and polycarbonates, we considered derivatives of tyrosine dipeptide as potential monomers. Our experimental rationale was based on the assumption that a diphenol derived from natural amino acids may be less toxic than many of the industrial diphenols. After protection of the amino and carboxylic acid groups, we expected the dipeptide to be chemically equivalent to conventional diphenols. In preliminary studies (14) this hypothesis was confirmed by the successful preparation of poly(Z-Tyr-Tyr-Et iminocarbonate) from the protected tyrosine dipeptide Z-Tyr-Tyr-Et (Figure 3). Unfortunately, poly (Z-Tyr-Tyr-Et iminocarbonate) was an insoluble, nonprocessible material for which no practical applications could be identified. This result illustrated the difficulty of balancing the requirement for biocompatibility with the need to obtain a material with suitable "engineering" properties. 

Due to its wide application in peptide synthesis, 1-hydroxybenzotriazole 1001 is the most commonly used benzo-triazole derivative with hundreds of references in Chemical Abstracts each year. Utility of compound 1001 comes from its readiness to form esters with carboxylic acids in the presence of dehydrating agents (DAs). Obtained esters 1002 react eagerly with amines to produce amides 1003 in high yields (Scheme 165). More details about this application are given in Section 5.01.12. 

The Friedel-Crafts acylation of aromatic compounds is an important synthesis route to aromatic ketones in the production of fine and specialty chemicals. Industrially this is performed by reaction of an aromatic compound with a carboxylic acid or derivative e.g. acid anhydride in the presence of an acid catalyst. Commonly, either Lewis acids e.g. AICI3, strong mineral acids or solid acids e.g. zeolites, clays are used as catalysts however, in many cases this gives rise to substantial waste and corrosion difficulties. High reaction temperatures are often required which may lead to diminished product yields as a result of byproduct formation. Several studies detail the use of zeolites for this reaction (1). 

Carboxylic acids, compounds of the type RCOH, constitute one of the most frequently encountered classes of organic compounds. Countless natural products are carboxylic acids or are derived from them. Some carboxylic acids, such as acetic acid, have been known for centuries. Others, such as the prostaglandins, which are powerful regulators of numerous biological processes, remained unknown until relatively recently. Still others, aspirin for example, are the products of chemical synthesis. The therapeutic effects of aspirin, welcomed long before the discovery of prostaglandins, are now understood to result from aspirin s ability to inhibit the biosynthesis of prostaglandins. 

Typically MCRs allow the synthesis of very many derivatives of a special scaffold. Since the number of possible products increases exponentially with the multiplicity of the MCR, very large chemical spaces can be inspected. These very large chemical spaces are not realistically accessible by classical sequential syntheses. As realized by Ugi in 1961 starting with 1000 each of the educts carboxylic acid, amines, aldehydes and isocyanides 10004 products are accessible [4]. In this seminal paper the roots of combinatorial chemistry are described. The authors noted that MCRs have huge variability. Although the paper describes the essentials of combinatorial chemistry, the time was not right for the great advances that only started 30 years later. 

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