Methylene glutaric acid

Acryhc esters dimerize to give the 2-methylene glutaric acid esters catalyzed by tertiary organic phosphines (37) or organic phosphorous triamides, phosphonous diamides, or phosphinous amides (38). Yields of 75—80% dimer, together with 15—20% trimer, are obtained. Reaction conditions can be varied to obtain high yields of trimer, tetramer, and other polymers. 

An example of this isomerization involving the thermal rearrangement of a polymeric anhydride of tranj-1,2-dimethylcyclopropane-l, 2-dicar-boxylic acid to a corresponding anhydride of y-methyl-a-methylene glutaric acid was described as early as 1934 von Auwers, K. Ungemach, O. Liebigs Ann. Chem. 1934, 511, 152. McGreer, D. E. Chiu, N. W. K. McDaniel, R. S. Proc. Chem. Soc. London 1964, 415. 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

Several procedures for making glutaric acid have been described in Organic Syntheses starting with trimethylene cyanide (28), methylene bis (malonic acid) (29), y-butyrolactone (30), and dihydropyran (31). Oxidation of cyclopentane with air at 140° and 2.7 MPa (400 psi) gives cyclopentanone and cyclopentanol, which when oxidized further with nitric acid at 65—75° gives mixtures of glutaric acid and succinic acid (32). 

Miscellaneous Derivatives. Fimehc acid is used as an intermediate in some pharmaceuticals and in aroma chemicals ethylene brassylate is a synthetic musk (114). Salts of the diacids have shown utUity as surfactants and as corrosion inhibitors. The alkaline, ammonium, or organoamine salts of glutaric acid (115) or C-5—C-16 diacids (116) are useflil as noncorrosive components for antifreeze formulations, as are methylene azelaic acid and its alkah metal salt (117). Salts derived from C-21 diacids are used primarily as surfactants and find apphcation in detergents, fabric softeners, metal working fluids, and lubricants (118). The salts of the unsaturated C-20 diacid also exhibit anticorrosion properties, and the sodium salts of the branched C-20 diacids have the abUity to complex heavy metals from dilute aqueous solutions (88). 

An angiotensin-converting enzyme inhibitor 64 was prepared in several steps from L-pyroglutamic acid. The formation of the bicyclic system was achieved with methylene glutaric anhydride (89TL3621). 

Many methods have been mentioned in the literature for the preparation of glutaric acid. Of these, the only methods of preparative interest are the hydrolysis of trimethylene cyanide with acids or alkalies,1 the hydrolysis of methylene dimalonic ester2 or methylene dicyanoacetic ester,3 and the oxidation of cyclopentanone with nitric acid.4 In this country the cheapness of trimethylene glycol makes it the best source for glutaric acid. The method described in the procedure is a modification of that originally described by Reboul.5... 

Besides MMCM and GM, two other coenzyme B -dependent carbon skeleton mutases are known. These are (1) methylene glutarate mutase (MGM) from the anaerobe Eubacterium (Clostridium) barkeri, which catalyzes the equilibration of 2-methylene-glutarate with (R)-3-methylitaconate as part of a degradative path of nicotinic acid [175,199] and (2) isobutyryl-CoA mutase (ICM), which is observed in species of gram-positive bacteria Strep-tomyces and catalyzes the reversible rearrangement of iso-butyryl-CoA and n-butyryl-CoA [177]. The isomerization of iso-butyryl-CoA and n-butyryl-CoA in ICM is relevant in the biosynthesis of polyketide antibiotics [177]. 

Because common names are frequently used with simple dicarboxylic acids, a few examples are noted. The first nine dicarboxylic acids have common names that must also be learned. Table 16.1 shows several common dicarboxylic acids, along with their common names and their lUPAC names. Oxalic acid (45) is the common name for the dicarboxylic acid with two carboxyl groups directly attached to each other, and malonic acid (46) has one -CHg- (methylene) unit separating the carboxyl units. As the number of methylene spacers increases, we see succinic acid (47), glutaric acid (48), etc. (all common names). The lUPAC names for these compounds are based on the total number of carbon atoms and the use of di to indicate the presence of two functional groups. 

To indicate the presence of two COOH units, the oic acid suffix of a mono-carboxylic acid is replaced with dioic acid. Oxalic acid therefore becomes 1,2-ethanedioic acid and malonic acid becomes 1,3-propanedioic acid. Similarly, succinic acid is 1,4-butanedioic acid and glutaric acid is 1,5-pentanedioic acid. With two carboxylic units, the dicarboxylic acids with five or fewer carbons have reasonable water solubility, reflecting their highly polar nature and ability to hydrogen bond. As the nrunber of methylene groups increases, the solubility in water decreases as expected. 

In addition to decarboxylation, the oxidation of acids yields hydro-peroxy, hydroxy, keto groups, lactones, and mono- and dicarboxylic acids of lower molecular weight. The mechanism of the oxidation of acids is similar to that for hydrocarbons. The reactivity of mono- [300] and dicarboxylic acids [216] with respect to cumylperoxy radicals was measured by oxidation in the presence of cumyl hydroperoxide as source of R02 (see Table 15). The reactivities of methylenic groups in mono- and dicarboxylic acids and in rc-paraffin acids are close. For example, at 100° C, feCH2 X 102 (1 mole-1 s-1) = 4.8 (n-decane), 10.0 (glutaric, sebacic, j3,7 groups), 6.4 (a-CH2 of dibasic acids), 8.0 (for monocarboxylic acids), and 11.0 (>CH2 for propionic acid). 

Diacetylene fatty acids were purchased from GFS. N-(2-Hydroxyethyl)-10,12-pentacosadiynamide (10) was synthesized by literatnre methods (77). 1-Amino-10,12-pentacosadiyne (11) was synthesized in fom steps from 10,12-pentacosadiynoic acid the acid in anhydrous tetrahydrofuran (THF) at 0 °C was reduced to the alcohol through treatment with hthinm alnminnm hydride (LAH, 2.5 equivalents) in diethyl ether for two hours, the alcohol was then converted to the mesylate by treatment with mesyl chloride (6 eqnivalents) in methylene chloride with diisopropyl ethyl amine over 30 minntes, the mesylate was displaced by sodium azide (1.5 equivalents) in dimethyl formamide (DMF) at 70 °C over one hour and the azide, in THF, was reduced to the amine with LAH (2 equivalents) in diethyl ether at 0 °C over one hour. N-(10,12-pentacosadiynyl)-glutamic acid (12) was prepared from 11 as follows 11 was reacted with glutaric anhydride (2 equivalents) in DMF, in the presence of diisopropylethylamine (3 equivalents), at 70 °C for 1 hour and the crade product recrystallized from a mixture of chloroform and hexanes. The identity of products were confirmed by H and C NMR. 

Using different aliphatic diacids with increasing number of methylene imits (X), from succinic with two methylene units to sebacic acid with eight methylene units, a series of polyesters of 1,3-propanediol was prepared. Thus, poly(propylene succinate) (X=2), poly (propylene glutarate) (X=3), poly(propylene adipate) (X=4), poly(propylene pimelate) (X=5), poly (propylene suberate) (X=6), poly (propylene azelate) (X=7) and poly(propylene sebacate) (X=8) samples have been synthesized. 

Scheme 14 Radical addition reactions to 1-methylene-3-alkyl-dimethyl glutarates in the presence and absence of a chelating Lewis acid.

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