Acid/thiol catalysts

Arthur L. Weber (1998), now working at the Seti Institute of the Ames Research Center at Moffett Field, reports the successful synthesis of amino acid thioesters from formose substrates (formaldehyde and glycolaldehyde) and ammonia synthesis of alanine and homoserine was possible when thiol catalysts were added to the reaction mixture. On the basis of his experimental results, Weber (1998) suggests the process shown in Fig. 7.10 to be a general prebiotic route to amino acid thioesters. 

The importance of the electron transfer reaction between RS" and an electron acceptor (Reactions 2 and 3) has been amply confirmed by the observation that the least acidic thiols are least resistant to oxidation (2), and by the enormously enhanced rate of reaction in the presence of redox catalysts, such as transition metal ions (13) or organic redox additives (14). In these latter cases, reactions of the type below become important,... 

In enzymes, the most common nucleophilic groups that are functional in catalysis are the serine hydroxyl—which occurs in the serine proteases, cholinesterases, esterases, lipases, and alkaline phosphatases—and the cysteine thiol—which occurs in the thiol proteases (papain, ficin, and bromelain), in glyceraldehyde 3-phosphate dehydrogenase, etc. The imidazole of histidine usually functions as an acid-base catalyst and enhances the nucleophilicity of hydroxyl and thiol groups, but it sometimes acts as a nucleophile with the phos-phoryl group in phosphate transfer (Table 2.5). 

Based on the analyses of the trace contaminants conducted on the wheat millfeed-derived products, numerous potential problem components were identified, relative to catalyst activity (3). These components (shown in Table 1) include sulfate (potential for metal sulfide formation) calcium, magnesium, and phosphate (potential for catalyst pore plugging by insoluble salt precipitation) sodium or potassium (alkali attack on the catalyst support) organic nitrogen components, such as amino acids (thiol... 

The protonation of a thiolate donor, formation of a nonclassical r 2-H2 complex, release of H2 and addition of D2, and the heterolytic cleavage of this D2 by the concerted attack of the Lewis acidic metal center and the Brpnsted basic thiolate donor are essential steps. The acidic thiol deuteron can exchange with EtOH protons. The resulting free protons and the deuteride complex yield HD and the coordinatively unsaturated species that is the actual catalyst. The detailed mechanism comprises a considerably larger number of steps (and equilibria) (143). For example, the occurrence of r 2-D2 and [M(D)(SD)] intermediates that exchange with H+ should give rise to [M(D)(SH)]... 

Acid zeolite catalysts offer a very good alternative for the clean synthesis of these sulfur containing substances. A suitable feed stock is the 4-isopropenyl-l-methyl-1-cyclohexene. In the presence of a commercial beta-zeolite (25) hydrogen sulfide is added to the autoclave at a reaction temperature of 50°C at a pressure of 17 bar. The conversion is 65.1% and the selectivity to 1-p-menthene-8-thiol is 43.9%. These are very promising results and they can be improved by using a commercial H-US-Y zeolite which rendered a conversion of 76.8% and a selectivity of 64.3% (62). 

Very recently, Nakajima and Okawa 164) investigated the hydrolysis of PNPA by Cyclo-(His-Glu-Cys-D-Phe-Gly)2. The second-order rate constant for the hydrolysis at pH 7.73 and 25 C was 19.61 M min for the cyclic decapeptide diacetate, which wt(s larger than 6.05 min for the corresponding linear pentapeptide triacetate and 1.33 M min for histidine hydrochloride, but smaller than 32.20 M min for cystein hydrochloride. The pH-rate profile for the reaction catalyzed by the cyclic decapeptide was bell-shaped with the maximum around pH 7.6, which indicates that the cyclic decapeptide is an acid—bs catalyst. On the other hand, the reaction by the cyclic decapeptide obeyed the Michaelis-Menten kinetics (i57), wdiich was found to involve a weak binding of the substrate = 2.7xlO M) prior to the unimolecular step. It is possible for imidazole, carboxyl, and thiol functions to cooperate in the cat ysis by the cyclic decapeptide, but the determination of the solution conformation would not be an easy task because of the thirty mem-bered ring. 

Fig. 23.13 An example of acid/thiol-paired silica catalysts from Margelefsky et al. derived from surface-bound sultone rings [33]...

In addition to n-alanine and n-glutamate, many bacterial cell walls also contain meso-diaminopimelate (DAP) [2]. DAP is produced by epimerization from l,l-DAP to d,l-DAP by the cofactor independent diaminopimelate epimerase [97, 98]. The structure of this enzyme has been solved and two cysteines in the active site were proposed to be the acid-base catalysts [99]. The pattern of label incorporation from tritiated water is consistent with a two-base mechanism [97]. The enzyme has been shown to be stoichiometrically inhibited by the thiol alkylating agent aziDAP [97]. Interestingly, DAP epimerase has an equilibrium constant of 2 (Keq = [d,l]/[l,l]) duc to the statistically expected higher concentration of the [d,l] form at equilibrium between these species [100]. 

The most common fluorotags (fluorescent reagents) are dansyl chloride and o-phthalaldehyde (OPA). Chromotags include p-bromophenacyl bromide (PBPB) for derivatization of carboxylic acids (K-salts) with a crown ether catalyst, ninhydrin for primary amines forming complexes that have their adsorption maxima at about 570 nm, and dansyl chloride for primary and secondary amines, including amino acids, thiols, imidazoles, phenols, and aliphatic alcohols. 

Because of the huge importance of pyridine derivatives, a considerable amoimt of effort has been directed to the development of multicomponent routes for their synthesis, including reactions performed in water. For instance, a one-pot four-component condensation of aldehydes, malononitrile and thiophenols in the presence of boric acid as catalyst in aqueous medium afforded high yields of 2-amino-3,5-dicaibonitrile-6-thiopyridines 46 [29], either by conventional heating or under ultrasound-aided conditions (Scheme 1.21). This reaction can also be performed in an aqneons snspension of basic almnina [30] or in water with microporous mo-lecnlar sieves as catalysts [31]. Mechanistically, this transformation involves an initial Knoevenagel condensation of the aldehyde with a molecule of malononitrile, followed by the Michael addition of the second molecule of malononitrile, reaction of one of the nitrile groups with the thiol, cyclization and a final air oxidation step. 

Reactions (2) and (3) require higher temperatures (280 °C). Instead of ammonia and carbon monoxide, formamide also can be used [501]. In table 49 some derivatives of saturated carboxylic acids obtained from carboxylic acids, thiols, amines and HCl are listed. Reaction (4) proceeds at moderate temperatures e.g. at 170 °C [531] or at 100 °C [512, 523]. The catalyst can be recycled several times [512]. 

More recently. Miller and coworkers reported that ortho-mercaptobenzoic acid and ortho-mercaptophenols 159 could be used as efficient thiol catalysts in both the intramolecular MBH and Rauhut-Currier reaction and they also demonstrated that chiral mercaptophenol afforded the reaction with low to moderate enantiose-lectivities (Scheme 31.53) [64]. Under estabhshed conditions, chiral catalysts (S)-and (R)-160 afforded high yields and moderate asymmetric inductions in the MBH reactions. The obtained enantioselectivities remained largely unaffected by the amount of water and base added, catalyst loading, and substrate concentration but were markedly influenced by the reaction temperature. Interestingly, both increasing and decreasing the temperature from the established value of 70 °C resulted in lower ee values. The complete absence of catalytic activity of (R)-161 further emphasizes the crucial importance of a protic substituent at the ortho-position to the nucleophilic thiol. 

Acetoiicetyliition Reactions. The best known and commercially most important reaction of diketene is the aceto acetylation of nucleophiles to give derivatives of acetoacetic acid (Fig. 2) (1,5,6). A wide variety of substances with acidic hydrogens can be acetoacetylated. This includes alcohols, amines, phenols, thiols, carboxyHc acids, amides, ureas, thioureas, urethanes, and sulfonamides. Where more than one functional group is present, ring closure often follows aceto acetylation, giving access to a variety of heterocycHc compounds. These reactions often require catalysts in the form of tertiary amines, acids, and mercury salts. Acetoacetate esters and acetoacetamides are the most important industrial intermediates prepared from diketene. 

Acid-Gatalyzed Synthesis. The acid-catalysed reaction of alkenes with hydrogen sulfide to prepare thiols can be accompHshed using a strong acid (sulfuric or phosphoric acid) catalyst. Thiols can also be prepared continuously over a variety of soHd acid catalysts, such as seoHtes, sulfonic acid-containing resin catalysts, or aluminas (22). The continuous process is utilised commercially to manufacture the more important thiols (23,24). The acid-catalysed reaction is commonly classed as a Markownikoff addition. Examples of two important industrial processes are 2-methyl-2-propanethiol and 2-propanethiol, given in equations 1 and 2, respectively. 

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