Fumaric acid hydrogen bonding

Maleic and fiimaric acids have physical properties that differ due to the cis and trans configurations about the double bond. Aqueous dissociation constants and solubiUties of the two acids show variations attributable to geometric isomer effects. X-ray diffraction results for maleic acid (16) reveal an intramolecular hydrogen bond that accounts for both the ease of removal of the first carboxyl proton and the smaller dissociation constant for maleic acid compared to fumaric acid. Maleic acid isomerizes to fumaric acid with a derived heat of isomerization of —22.7 kJ/mol (—5.43 kcal/mol) (10). The activation energy for the conversion of maleic to fumaric acid is 66.1 kJ/mol (15.8 kcal/mol) (24). 

An example of intramolecular hydrogen bonding is provided by the cis- and trans- forms of the acid HOOC—CH=CH—COOH. The trans- form, fumaric acid, has a higher melting point than the cis- form, maleic acid. In addition to the general effect of molecular shape (mentioned earlier in this chapter), another reason for... 

This intramolecular bonding in maleic acid, (8), halves its ability to form intermolecular bonds. In fumaric acid, on the other hand, all of the hydrogen bonds form between molecules (intermolecular bonds) to give a stronger, interlinked crystal structure. 

Detailed studies of 1 1 complex formation between and maleic and fumaric acids, which precedes reduction to succinic acid, cis-trans isomerisation and exchange of the double bond hydrogens, are relevant to the complex kinetics (A = substrate)... 

The aromatic spacer group of the model receptors prevent the formation of intramolecular hydrogen bonds between the opposing carboxyls yet these functions are ideally positioned for intermolecular hydrogen bonds of the sort indicated in 32. The acridine derivatives do indeed form stoichiometric complexes with oxalic, malonic (and C-substituted malonic acids) as well as maleic and phthalic acids, Fumaric, succinic or glutaric acids did not form such complexes. Though protonation appears to be a necessary element in the recognition of these diacids, the receptor has more to... 

Elving, Rosenthal, Hayes and Martin 41> studied the electrochemical reduction of bromofumaric acid(27) and bromomaleic acid(28)in aqueous solution over a wide pH range. It was claimed that reduction of 27 proceeds stereo-specifically to fumaric acid, and that reduction of 28 affords mixtures of maleic and fumaric acids. Because of the polar and hydrogen-bonding properties of the carboxyl groups in 27 and 28, the relation of these results to those of Fry and Mitnick l6) is unclear. 

The effect is very pronounced, but falls off sharply as soon as the carboxyl groups are separated by more than one saturated carbon atom. C/ s-butenedioic(maleic) acid (5, pKal = 1-92) is a much stronger acid than trans-butenedioic(fumaric) acid (6, pX,1 = 3-02), due to the intramolecular hydrogen bonding that can take place with the former, but not with the latter, leading to relative stabilisation of the cis (maleate, 7) mono-anion (cf. o-hydroxybenzoic acid above) ... 

Figure 10-9 Representation of the course of enzyme-induced hydration of fumaric acid (trans-butenedioic acid) to give L-malic acid (L-2-hydroxy-butanedioic acid). If the enzyme complexes with either—C02H (carboxyl) group of fumaric acid, and then adds OH from its right hand and H from its left, the proper stereoisomer (l) is produced by antarafacial addition to the double bond. At least three particular points of contact must occur between enzyme and substrate to provide the observed stereospecificity of the addition. Thus, if the enzyme functions equally well with the alkenic hydrogen or the carboxyl toward its mouth (as shown in the drawing) the reaction still will give antarafacial addition, but o,L-malic acid will be the product.

The stereochemistry of cathodic hydrogenation is thus far not predictable or explainable. There is a preponderance for trans addition in the reduction of al-kynes, while cis addition occurs predominantly with cis- and trans-stilbene and maleic acid derivatives. On the other hand, dimethylmaleic acid and dimethyl-fumaric acid are exclusively hydrogenated to the trans products, meso- and dl-di-methylsuccinic acid 302 With a silver-palladium cathode in 5% aquous sulfuric acid triple bonds are reduced in a specific cis addition to double bonds 303 ... 

The XH NMR spectrum for fumaric acid contains two lines, assigned to the olefinic and carboxylic acid protons, the latter of which is characterised by the same O- -O distance and has the same Siso value as the intermolecular hydrogen bond in maleic acid. 

In an alkene such as ethene, the presence of the 7t-bond prevents rotation about the C=C bond. The hydrogen atoms on the separate carbons are either cis or trans to each other. When the alkene bears substituents on the separate carbon atoms, these are cis or trans to each other. Distinct geometric isomers are possible. These compounds have different properties. Thus c -ethenedicarboxylic acid is maleic acid (1.23). The carboxyl groups are close together in space and react together to form a cyclic anhydride (1.24). On the other hand, tranj-ethenedicarboxylic acid is fumaric acid (1.25) and no such interaction is possible. 

An X-ray analysis (138) of racemic (fumaric acid)Fe(CO)4 shows a trigonal bipyramidal arrangement of the five ligands about the iron atom with the double bond at an equatorial position (63). The complex molecules are hydrogen-bonded through the fumaric acid ligands. Unlike... 

The crystal of (—)-(fumaric acid)Fe(CO)4 contains three crystallo-graphically distinct complex molecules. A, B, and C, each of which has C2 symmetry (139). As in the racemate, the four carbon atoms of the fumaric acid are not coplanar, but show dihedral angles of 151°, 148°, and 146° in molecules A, B, and C, respectively. Although the axis of the double bond in molecules A and C is significantly tilted out of the equatorial plane of the complex, that of molecule B is not. The different coordinations are presumably stabilized by different arrangements of the hydrogen bonds (139). 

Childs et al. formulated crystalline complexes with a salt form of an API with carboxylic acids. The antidepressant, fluoxetine hydrochloride, was cocrystallized with benzoic acid, succinic acid, and fumaric acid where the chloride ion acts as a hydrogen bond acceptor for the carboxylic acid groups of the three ligands. Intrinsic dissolution studies were carried out at 10°C because at 25°C, the rates were so rapid that the dissolution rates of the cocrystals could not be distinguished from one another. The fumaric acid 2 1 complex had a similar dissolution rate to that of the crystalline fluoxetine hydrochloride, but the dissolution rate for the benzoic acid 1 1 complex was half that of fluoxetine hydrochloride. Fluoxetine hydrochloride succinic acid 2 1 complex had approximately three times higher dissolution rate, but the dissolution was so fast that an accurate value was difficult to measure. ... 

Figure 2.3.10 Ball-and-stick representation of a single hydrogen-bonded assembly involving fumaric acid (a) before reaction and (b) after complete reaction.

MacGillivray and co-workers have recently demonstrated that the linear template approach can also be expanded to hydrogen-bond acceptor templates. In particular, co-crystallization of 2,3-bis(4-thiopyridylmethyl)naphthalene as a template with fumaric acid as the reactant produced a finite, four-component molecular assembly held together by O-H N hydrogen bonds (Fig. 2.3.10(a)) [57]. The double bonds of the stacked fumaric acid molecules were aligned suitably for a photodimerization that proceeded, upon UV-irradiation with 300 nm light, in a SCSC fashion to a maximum of 36% yield. The photoreaction provided, stereospecifically, the rctt isomer of 1,2,3,4-cyclobutane-tetracarboxylic acid (Fig. 2.3.10(b)). 

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