Table side chains

It is noteworthy that the compounds which have been shown to undergo extensive acetoxylation or side-chain nitration, viz. those discussed above and hemimellitene and pseudocumene (table 5.4), are all substances which have an alkylated ring position activated towards electrophilic attack by other substituents. 

Table 20. Protection of amino acid side-chains.

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

The best procedures for 3-vinylation or 3-arylation of the indole ring involve palladium intermediates. Vinylations can be done by Heck reactions starting with 3-halo or 3-sulfonyloxyindoles. Under the standard conditions the active catalyst is a Pd(0) species which reacts with the indole by oxidative addition. A major con.sideration is the stability of the 3-halo or 3-sulfonyloxyindoles and usually an EW substituent is required on nitrogen. The range of alkenes which have been used successfully is quite broad and includes examples with both ER and EW substituents. Examples are given in Table 11.3. An alkene which has received special attention is methyl a-acetamidoacrylate which is useful for introduction of the tryptophan side-chain. This reaction will be discussed further in Chapter 13. 

The haloalkane dehydrogenase is believed to act by using one of its side chain carboxylates to dis place chloride by an Sn2 mechanism (Recall the reac tion of carboxylate ions with alkyl halides from Table 8 1 )... 

You will recognize the side chain oxidation of p xylene to terephthahc acid as a reaction type discussed previously (Section 11 13) Examples of other reactions encoun tered earlier that can be applied to the synthesis of carboxylic acids are collected m Table 19 4... 

FIGURE 27 1 Electro static potential maps of the 20 common amino acids listed in Table 27 1 Each ammo acid is oriented so that Its side chain is in the upper left corner The side chains affect the shape and properties of the ammo acids... 

Some ammo acids have side chains that bear acidic or basic groups As Table 27 3 indicates these ammo acids are characterized by three values The third pK reflects the nature of the side chain Acidic ammo acids (aspartic and glutamic acid) have acidic side chains basic ammo acids (lysine arginine and histidine) have basic side chains The isoelectric points of the ammo acids m Table 27 3 are midway between the pK values of the zwitterion and its conjugate acid Take two examples aspartic acid and lysine Aspartic acid has an acidic side chain and a pi of 2 77 Lysine has a basic side chain and a pi of 9 74... 

Several of the ammo acids listed m Table 27 1 bear side chain functional groups which must also be protected during peptide synthesis In most cases protecting groups are available that can be removed by hydrogenolysis... 

Mechanical and Thermal Properties. The first member of the acrylate series, poly(methyl acrylate), has fltde or no tack at room temperature it is a tough, mbbery, and moderately hard polymer. Poly(ethyl acrylate) is more mbberflke, considerably softer, and more extensible. Poly(butyl acrylate) is softer stiU, and much tackier. This information is quantitatively summarized in Table 2 (41). In the alkyl acrylate series, the softness increases through n-octy acrylate. As the chain length is increased beyond n-octy side-chain crystallization occurs and the materials become brittle (42) poly( -hexadecyl acrylate) is hard and waxlike at room temperature but is soft and tacky above its softening point. 

Ring- or side-chain fluoriaated nitrogen heterocycHcs have been iacorporated iato crop-protection chemicals, dmgs, and reactive dyestuffs. Key iatermediates iaclude fluoriaated pyridines, quiaolines, pyrimidines, and tria2iaes. Physical properties of some fluoriaated nitrogen heterocycHcs are Hsted ia Table 13. 

Increa sing the bulkiness of the alkyl group from the esterifying alcohol in the ester also restricts the motion of backbone polymer chains past each other, as evidenced by an increase in the T within a series of isomers. In Table 1, note the increase in T of poly(isopropyl methacrylate) over the / -propyl ester and similar trends within the butyl series. The member of the butyl series with the bulkiest alcohol chain, poly(/-butyl methacrylate), has a T (107°C) almost identical to that of poly(methyl methacrylate) (Tg = 105° C), whereas the butyl isomer with the most flexible alcohol chain, poly( -butyl methaciylate), has a T of 20°C. Further increase in the rigidity and bulk of the side chain increases the T. An example is poly(isobomyl methacrylate)... 

Much of protein engineering concerns attempts to explore the relationship between protein stmcture and function. Proteins are polymers of amino acids (qv), which have general stmcture +H3N—CHR—COO , where R, the amino acid side chain, determines the unique identity and hence the stmcture and reactivity of the amino acid (Fig. 1, Table 1). Formation of a polypeptide or protein from the constituent amino acids involves the condensation of the amino-nitrogen of one residue to the carboxylate-carbon of another residue to form an amide, also called peptide, bond and water. The linear order in which amino acids are linked in the protein is called the primary stmcture of the protein or, more commonly, the amino acid sequence. Only 20 amino acid stmctures are used commonly in the cellular biosynthesis of proteins (qv). 

In the case of l,4-ben2oquinone, the product is steam-distilled, chilled, and obtained in high yield and purity. Direct oxidation of the appropriate unoxygenated hydrocarbon has been described for a large number of ring systems, but is generally utilized only for the polynuclear quinones without side chains. A representative sample of quinone uses is given in Table 5. 

OC-Methylstyrene. This compound is not a styrenic monomer in the strict sense. The methyl substitution on the side chain, rather than the aromatic ring, moderates its reactivity in polymerization. It is used as a specialty monomer in ABS resins, coatings, polyester resins, and hot-melt adhesives. As a copolymer in ABS and polystyrene, it increases the heat-distortion resistance of the product. In coatings and resins, it moderates reaction rates and improves clarity. Physical properties of a-methylstyrene [98-83-9] are shown in Table 12. 

Monomer Reactivity. The nature of the side chain R group exerts considerable influence on the reactivity of vinyl ethers toward cationic polymerization. The rate is fastest when the alkyl substituent is branched and electron-donating. Aromatic vinyl ethers are inherently less reactive and susceptible to side reactions. These observations are shown in Table 2. 

As shown in Table 3, the glass-transition temperatures of the amorphous straight-chain alkyl vinyl ether homopolymers decrease with increasing length of the side chain. Also, the melting points of the semicrystalline poly(alkyl vinyl ether)s increase with increasing side-chain branching. 

AH cephalosporins found in nature (Tables 1 and 2) have the D-a-aminoadipic acid 7-acyl side chain (21). AH of these compounds can be classified as having rather low specific activity. A substantial amount of the early work in the cephalosporin area was unsuccessfiiHy directed toward replacing the aminoadipic acid side chain or modifying it appropriately by fermentation or enzymatic processes (6,22). A milestone ia the development of cephalosporins occurred in 1960 with the discovery of a practical chemical process to remove the side chain to afford 7-ACA (1) (1). Several related processes were subsequendy developed (22,23). The ready avaHabHity of 7-ACA opened the way to thousands of new semisynthetic cephalosporins. The cephalosporin stmcture offers more opportunities for chemical modification than does that of penicillins There are two side chains that especiaHy lend themselves to chemical manipulation the 7-acylamino and 3-acetoxymethyl substituents. 

Substitution of penicillins by 6a-methoxy was found to be compatible with an a-acidic side chain in terms of antibacterial activity, but less beneficial when the side chain contained an a-acyl or a-ureido substituent. However, analogues of the ureido penicillin VX-VC-43 (Table 2) containing a 6a-methoxy substituent (10) were found to combine good stabiUty to P-lactamase and relatively high antibacterial activity (37). Following an extensive program to identify other 6a-substituents that would stabilize the acyl and ureido series of penicillins, the 6a-formamido series (11) represented by formidacillin (BRL 36650) (Table 2) was developed (38). 

Compounds available in the United States are Hsted in Table 1. Whereas they vary in degree, all of them share similar HabiUties of cardiovascular side effects, the potential for central nervous system (CNS) stimulation, the development of tolerance, and abuse potential. AH, with the exception of ma2indol, are derivatives of phenethylamine. The introduction of an oxygen atom on the -carbon of the side chain tends to reduce CNS stimulant properties without decreasing the anorectic activity. Following the Federal Controlled Dmg Act of 1970, dmgs were classified into one of five schedules according to medical utiUty and abuse potential. 

Table 3. Toxicology of Side-Chain Chlorinated Toluenes...

Ring-Substituted Derivatives The ring-chlorinated derivatives of benzyl chloride, benzal chloride, and benzotrichloride are produced by the direct side-chain chlorination of the corresponding chlorinated toluenes or by one of several indirect routes if the required chlorotoluene is not readily available. Physical constants of the main ring-chlorinated derivatives of benzyl chloride, benzal chloride, and benzotrichloride are given in Table 4. 

En2yme techniques are primarily developed for commercial reasons, and so information about immobilisation and process conditions is usually Limited. A commercially available immobilised penicillin V acylase is made by glutaraldehyde cross-linking of a cell homogenate. It can be used ia batch stirred tank or recycled packed-bed reactors with typical operating parameters as iadicated ia Table 2 (38). Further development may lead to the creation of acylases and processes that can also be used for attaching side chains by ensymatic synthesis. 

A number of examples of monoacylated diols produced by enzymatic hydrolysis of prochiral carboxylates are presented in Table 3. PLE-catalyzed conversions of acycHc diesters strongly depend on the stmcture of the substituent and are usually poor for alkyl derivatives. Lipases are much less sensitive to the stmcture of the side chain the yields and selectivity of the hydrolysis of both alkyl (26) and aryl (24) derivatives are similar. The enzyme selectivity depends not only on the stmcture of the alcohol, but also on the nature of the acyl moiety (48). 

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