Pimelic acid

This is the clearest evidence there is at present to account for the effect of pimelic acid as a bacterial essential nutrient. The particular strains of C. dipMheriae which require pimelic acid as a nutrient are probably strains lacking the ability to synthesize biotin. And this defective synthetic power would appear to concern the fatty acid side chain of biotin, since when pimelic acid is provided, the rest of the molecule appears to be synthesized. This is supported by the finding that C. diphtheriae Allen strain, using pimelic acid, was not inhibited by the antibiotin factor avidin, whereas inhibition did occur when biotin was the external source of growth factor (see next section). (Cf. also 73a.) 

Numerous interesting consequences follow from the discovery of a naturally-occurring growth inhibitor such as Avidin, which throw an entirely new light on the problems of nutritional sufficiency. 

The use of specific inhibitors operative against essential metabolites opens a new route of attack for the discovery of the external growth factor requirements of bacteria and other organisms. Once an essential metabolite is Imown it may be possible deliberately to design specific growth inhibitors (90) or to find naturally-occurring ones, like the antibiotin factor these specific inhibitors will then enable a rapid survey of bacteria to be made to reveal their requirements for the specific essential metabolite. 

Since the antibiotin factor does not inhibit those bacteria which synthesize biotin, the antibiotin factor appears to combine only with the externally supplied biotin and cannot penetrate effectively to the sites of biotin synthesis and utilization. This is analogous to the findings with the synthetic inhibitory growth factor analogs (e.g., pyrithiamin and thiamin, pantoyl taurine and pantothenic acid, pyridine-2-sulfonamide and nicotinamide) where the inhibitory action is largely confined to those otgan-isms which do not synthesize the growth factor. 

---

Glutarlc acid (n =3), pimelic acid (n = 5) and suberic acid (n = 6) may be obtained from the corresponding dibromides. These are converted by aqueous - alcoholic potas-sium or sodium cyanide into the dinitriles, and this latter are smoothly hydrolysed by 50 per cent, sulphuric acid into the dicarboxybc acids ... 

Pimelic acid. This may be prepared from 1 5-peiitanediol or tetra-hydropyran, through the dibromide (Sections 111,35 and 111,37) and dinitrile exactly as described for Suberic Acid. An alternative method for the preparation of 1 5-dibromopentane, together with full details of the subsequent steps, is given in the following Section. 

Pimelic acid. Heat a mixture of 18 g. of pentamethylene dicyanide and 250 g. of 50 per cent, sulphuric acid by weight in a 750 ml. round-bottomed flask under reflux for 9 hours. INIost of the pimehc acid separates from the cold reaction mixture. Filter oflF the crystaUine acid upon a sintered glass funnel. Saturate the filtrate with ammonium sulphate and extract it with three 50 ml. portions of ether. Dissolve the residue on the filter (which is shghtly discoloured, but is fairly pure pimehc acid) in the combined ethereal extracts, dry with anhydrous sodium or magnesium sulphate, and remove the ether by distiUation. Recrystallise the residual sohd acid from benzene containing 5 per cent, of ether. The yield of pure pimehc acid, m.p, 105-106°, is 22 g. 

Sahcyhc acid, upon reaction with amyl alcohol and sodium, reduces to a ring-opened ahphatic dicarboxyhc acid, ie, pimelic acid (eq. 5). The reaction proceeds through the intermediate cyclohexanone-2-carboxyhc acid. This novel reaction involves the fission of the aromatic ring to i j -hexahydrosahcyhc acid when sahcyhc acid is heated to 310°C in an autoclave with strong alkah. Pimelic acid is formed in 35—38% yield and is isolated as the diethyl ester. 

Biotin is produced by a multistep pathway in a variety of fungi, bacteria, and plants (50—56). The estabUshed pathway (50,56) in E. coli is shown in Figure 6. However, Htde is known about the initial steps that lead to pimelyl-Co A or of the mechanism of the transformation of desthiobiotin to biotin. Pimelic acid is beheved to be the natural precursor of biotin for some microorganisms (51). 

Pimelic acid (heptane-1,7-dioic acid) [111-16-0] M 160.2, m 105-106 , pK 4.46, 5.58. Crystd from water or from benzene containing 5% diethyl ether. 

Even before heating all the acids rapidly appeared as blue zones on a yellow-blue background. After heating tartaric acid QiRf 2—5) and maUc acid hRf 5 — 10) retained their color while lactic acid hRf 30 — 35), succinic acid hRf 35—40), pimelic acid hRf 50), maleic acid hRf 55), suberic acid hRf 55 — 60), benzoic acid hRf 80 — 85), stearic acid hRf 85 — 90) and arachidic acid hRf 85—90) appeared as pale yellow zones on a blue-yellow background (Fig. 1). The detection limits lay at 1 to 2 pg substance per chromatogram zone. 

Fig. 1 Schematic representation of the chromatographic separation of carboxylic acids. Maleic acid (1), pimelic acid (2), succinic acid (3), benzoic acid (4), malic acid (5), tartaric acid (6), lactic acid (7), stearic acid (8), arachidic acid (9), suberic acid (10), mixture (M).

The application of this addition to aminomethylene ketones provides a convenient synthesis of monoamides of pimelic acid (508). It should be noted that the corresponding oxidation of hydroxy methylene cyclohexanone leads to ring contraction and formation of cyclopentanoic acid. 

Pimelin-keton, n, pimelic ketone (cyclohexanone), -saure,/. pimelic acid,... 

Pimelic Acid (Heptanedioic Acid or 1,5-Pentane-dicarboxytlc Acid). HOOC.(CH2)s.COOH mw 160.17 white prisms mp 106° bp 272° at 100mm (subl), and 212° at 10mm d 1.329 g/cc at 15°. Sol in w, ethanol, eth and hot benz. Prepn is by oxidn of cycloheptanone, capric acid or oleic acid treatment of salicylic acid with Na in amyl ale, or by decarboxylating 1,1,5,5-pentanetetracarboxylic acid with heat Pimelic acid has been combined with cis and trans-, 4-cyclohexanediol to give polyesters, and with m-xylene-ce,ol -diamine or poly-methylenediamines to form polyamides. With diperoxides, the acid forms resins. It is also used as the parent compd to form the expls presented below... 

DIETHYL y-OXOPIMELATE (Pimelic acid, y-oxo-, diethyl ester)... 

---