Succinates, synthesis

As an activator of the phosphokinases, magnesium is essential in energy-requiring biological processes, such as activation of amino acids, acetate, and succinate synthesis of proteins, fats, coen2ymes, and nucleic acids generation and transmission of nerve impulses and muscle contraction (67). 

Orjuela, A., Kolah, A., Hong, X., Lira, C. T., Miller, D. J. (2012). Diethyl succinate synthesis by reactive distillation. Separation and Purification Technology, 88, 151—162. 

Figure 17.15 Major metabolic pathways involved in SA production in Saccbaromyces cerevisiae. Bold arrows indicate the major routes for succinate synthesis starting from glucose (a) via the reductive TCA cycle and (b) via the giyoxyiate cycle. PEP, phos-phoenolpyruvate OAA, oxaloacetate MAL, malate FUM, fumarate Suc-CoA, sucdnyl-CoA cr-KG, cr-ketoglutarate ICT, isodtrate CIT, citrate, ppc, PEP carboxykinase pyc, pyruvate carboxylase pyk, pyruvate kinase ...

Gallmetzer, M., Meraner, J., Burgstaller, W, 2002. Succinate synthesis and excretion by Penidllium simplicissimum under aerobic and anaerobic conditions. FEMS Microbiology Letters 210 (2), 221-225. 

FiUol, L., Martmez-UtriUa, R., Miranda, M. A., and Morera, I., Photoph) ical versus aluminum chloride-catalyzed Fries rearrangement of aryl hydrogen succinates synthesis of 2( H)-furanones, Monatsh. Chem., 120, 863, 1989. 

A further example is given below illustrating the use of a dibasic anhydride (succinic anhydride) the succinoylation reaction is a valuable one since it leads to aroyl carboxylic acids and ultimately to polynuclear hydrocarbons. This general scheme of synthesis of substituted hydrocarbons through the use of succinic anhydride is sometimes called the Haworth reaction. Thus a-tetralone (see below) may be reduced by the Clemmensen method to tetralin (tetrahydronaphthalene) and the latter converted into naphthalene either catal3d.ically or by means of sulphur or selenium (compare Section, VI,33). 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

Succineins. Succineins are carboxyethyl-substituted pyronines made by substituting succinic anhydride for formaldehyde in the basic synthesis,... 

Pyrrohdinone (2-pyrrohdone, butyrolactam or 2-Pyrol) (27) was first reported in 1889 as a product of the dehydration of 4-aminobutanoic acid (49). The synthesis used for commercial manufacture, ie, condensation of butyrolactone with ammonia at high temperatures, was first described in 1936 (50). Other synthetic routes include carbon monoxide insertion into allylamine (51,52), hydrolytic hydrogenation of succinonitnle (53,54), and hydrogenation of ammoniacal solutions of maleic or succinic acids (55—57). Properties of 2-pyrrohdinone are Hsted in Table 2. 2-Pyrrohdinone is completely miscible with water, lower alcohols, lower ketones, ether, ethyl acetate, chloroform, and benzene. It is soluble to ca 1 wt % in aUphatic hydrocarbons. 

With the saturated analogs, i.e. succinic anhydride and its derivatives, pyridazines are formed in only a few cases. The reaction has been applied to the preparation of perhydro-pyridazines and their 3,6-diones (68MI21200, 70JOC1468). For the synthesis of 4,5-dihalopyridazinones, /3-formylacrylic acids, for example mucochloric acid, are useful syn-thons (Scheme 80). 

When the 1-position is substituted, 3- and 5-aminopyrazoles react at the C-4 carbon atom, the reactivity of which is enhanced by the amino group. Thus pyrazolo[3,4-Z ]pyridines (545) are obtained either by the Skraup synthesis or from 1,3-diifunctional compounds. Here also aminopyrazolinones have been used instead of aminopyrazoles to prepare (545 R = OH). If 1,4-ketoesters (succinic acid derivatives) are used instead of /3-ketoesters, pyrazolo[3,4-Z ]azepinones (546) are obtained. 

FRANCHIMOND Cyano Succinic Acid Synthesis Condensation of a-haloesters to succinic acid derivalives in the presence of CN ... 

VOLHARDT ERDMANN Thiophene synthesis Thiophene synthesis from succinic acids... 

The synthesis of 2-hydroxycyclobutanone was chosen as a model for the use of a trapping agent because diethyl succinate was the most accessible of 1,2-diesters and because the hydrolysis step for this compound is more difficult than most. Procedures developed for succinoin have been found broadly applicable in preparation of other sensitive acy loins. 

Succinic Acid.—Taitailc acid, like malic acid, is converted into succinic and on reduction with HI, and the relationship of these three acids is thereby established. The constitution of siKcinii a( id itself has been determined by its synthesis fiom ethylene (Maxwell Simpson). Ethylene unites with bromine, fonnmg ethylene bioinidc, w hich yields ethylene cyanide with ])Otassium cyanide. I hc latter is then hydrolysed. 

In 1937 Krebs found that citrate could be formed in muscle suspensions if oxaloacetate and either pyruvate or acetate were added. He saw that he now had a cycle, not a simple pathway, and that addition of any of the intermediates could generate all of the others. The existence of a cycle, together with the entry of pyruvate into the cycle in the synthesis of citrate, provided a clear explanation for the accelerating properties of succinate, fumarate, and malate. If all these intermediates led to oxaloacetate, which combined with pyruvate from glycolysis, they could stimulate the oxidation of many substances besides themselves. (Kreb s conceptual leap to a cycle was not his first. Together with medical student Kurt Henseleit, he had already elucidated the details of the urea cycle in 1932.) The complete tricarboxylic acid (Krebs) cycle, as it is now understood, is shown in Figure 20.4. 

This is a crucial point because (as we will see) proton transport is coupled with ATP synthesis. Oxidation of one FADHg in the electron transport chain results in synthesis of approximately two molecules of ATP, compared with the approximately three ATPs produced by the oxidation of one NADH. Other enzymes can also supply electrons to UQ, including mitochondrial 5w-glyc-erophosphate dehydrogenase, an inner membrane-bound shuttle enzyme, and the fatty acyl-CoA dehydrogenases, three soluble matrix enzymes involved in fatty acid oxidation (Figure 21.7 also see Chapter 24). The path of electrons from succinate to UQ is shown in Figure 21.8. 

Engelhardt s experiments in 1930 led to the notion that ATP is synthesized as the result of electron transport, and, by 1940, Severo Ochoa had carried out a measurement of the P/O ratio, the number of molecules of ATP generated per atom of oxygen consumed in the electron transport chain. Because two electrons are transferred down the chain per oxygen atom reduced, the P/O ratio also reflects the ratio of ATPs synthesized per pair of electrons consumed. After many tedious and careful measurements, scientists decided that the P/O ratio was 3 for NADH oxidation and 2 for succinate (that is, [FADHg]) oxidation. Electron flow and ATP synthesis are very tightly coupled in the sense that, in normal mitochondria, neither occurs without the other. 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

The synthesis of porphyrins from dipyrrylmethenes was first developed by Fischer42 and his collaborators. Different variants of this method are available. For the preparation of centrosym-metric porphyrins 7, the self-condensation of 5-bromo-5 -methyldipyrrylmethene hydrobromides or perbromides 6 in organic acid melts like succinic acid, tartaric acid or formic acid at temperatures up to 200 °C can be used. 

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