Acid Oxidation State

Because the intermediates described in this section are reactive and potentially unstable compounds, the procedures describe the preparation of the active intermediate followed by a subsequent reaction rather than just the active intermediate. 

One of the most straightforward methods of activating acids via the acid chloride is by reacting the acid with oxalyl chloride and a catalytic amount of DMF. This reaction is fast and liberates a great deal of gas, so it is important that the reaction vessel is adequately vented it is also moderately exothermic and frequently requires cooling. As the intermediate acid chloride typically hydrolyzes on silica gel, the reaction can be monitored by first dropping an aliquot of the reaction mixture into methanol and then checking by TLC for disappearance of the acid and formation of the methyl ester. 

An advantage of phosphorous oxychloride in the preparation of acid chlorides is that no gas is evolved. As is demonstrated in the following example, basic nitrogens do not interfere with the reaction. 

Thionyl chloride costs less and liberates less gas than oxalyl chloride. 

Thionyl chloride (10.4 g, 87.4 mmol) was added to a mixture of biphenyl-2-carboxylic acid (15.0 g, 75.7 mmol) and DMF (0.28 g, 3.83 mmol) in toluene (72 mL) at an internal temperature of 40 °C. The mixture was stirred at this temperature for approximately 2 h. After completion of the reaction, the mixture was concentrated to dryness at 60 °C. The resultant residue was then diluted with toluene (36 mL) and concentrated to dryness at 60 °C, and the process was repeated again to give biphenyl-2-carbonyl chloride as an oil. Acetone (100 mL) was added to the oil, and 4-amino benzoic acid (10.4 g, 75.8 mmol) and /V, /V-d i m c th y I an i I i n c (10.1 g, 83.3 mmol) were added to the resultant solution at 25 °C. The mixture was stirred at this temperature for approximately 2 h. Water (100 mL) was then poured into the mixture, and it was stirred at 25 °C for more than 1 h. The resultant crystals were collected by filtration and dissolved in DMF (100 mL) at 25 °C. The solution was then filtered to remove insoluble materials, water (100 mL) was poured into the filtrate, and it was stirred at 25 °C for approximately 2 h. The resultant crystals were collected by filtration and dried at 40 °C to give the amide as white crystals (22.7 g, 95%). 

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Klapper, L., D. M. McKnight, J. R. Fulton, E. L. Blunt-Harris, K. P. Nevin, D. R. Lovely, and P. G. Hatcher. 2002. Fulvic acid oxidation state detection using fluorescence spectroscopy. Environmental Science Technology, in press. 

Although the aforementioned routes provided the desired y-amino acids, it was desirable to develop a synthesis which incorporates the carboxylic acid oxidation state prior to coupling. We hypothesized that manganese-mediated radical addition would accomplish this objective, and therefore initiated a study of manganese-mediated coupling of alkyl iodides with y-hydrazonoesters [104]. We had already shown that the manganese-mediated radical addition conditions offer excellent chemoselectivity, but it remained to be seen whether the stereocontrol model would be disrupted would an additional Lewis basic ester function in the hydra-zone interfere with the role of In(III) in two-point binding and rotamer control ... 

A number of thiocaibonyl compounds in the carboxylic acid oxidation state have been utilized in Diels-Alder reactions, but no systematic study in this area has been done. Some of the various structural types of thiocarbonyls which are reactive dienophiles are indicated in equations (90), (91) and (92).16s Reactions of this class show good to moderate regioselectivity, but relatively little is loiown with regard to stereoselectivity. Additional examples can be found in earlier reviews. ... 

With the exception of a few rare examples from the chemistry of molybdenum, manganese, rhenium, iron, and ruthenium, chelate complexes of O-func-tionalized cyclopentadienyl ligands have only been reported in this category for the very oxophilic group 4 metals, preferentially in their highest and most Lewis acidic oxidation state. Linked alkoxo— or aryloxo—cyclopentadienyl and ether—cyclopentadienyl systems are almost equally abundant for these metals. 

Several examples of oxidation of aromatic side chains are given in Scheme 9.16. Entries 3 and 5 are cases where the oxidation is terminated at stages short of the carboxylic acid oxidation state. 

The hydrogenation of functionalities in the carboxylic acid oxidation state can also be useful for small- or large-scale syntheses. For example, the hydrogenation of adiponitrile generates hexamethylenediamine that is one of the two monomers in the production of nylon. This reaction is conducted with a heterogeneous catalyst, but homogeneous catalysts for the reduction of nitriles to amines would be convenient for the conversion of nitriles to amines on a laboratory scale. The hydrogenation of esters to aldehydes would... 

The syntheses we have examined thus far do not take into account enantios-electivity. The Hannesian group described a synthesis that used quinic acid (165) as an enantiopure starting material. The idea was to prepare reserpine (79) from / mr -substituted cyclohexane 162. The incipient C3 was to come from an intermediate with that carbon at the aldehyde oxidation state (to be derived from reduction of the lactone). The incipient C21 was to be introduced at the carboxylic acid oxidation state. This plan avoids issues with formation of inside isomers as we saw in the Wender and Martin syntheses. Lactone 162 was to come via a radical cyclization of an intermediate of type... 

Three noteworthy procedures for the oxidation of an aldehyde to the acid oxidation state were recently reported. Jonathan M. J. Whhams of the University of Bath demonstrated Chem. Commun. 2008, 624) that crotonitrile could serve as the hydrogen acceptor in the oxidation of an aldehyde 7 to the methyl ester 8. Note that isolated alkenes were stable to these conditions. Vikas N. Telvekar the University Institute of Chemical Technology, Mumbai improved Tetrahedron Lett. 2008, 49, 2213) the oxidative amination of an aldehyde 9 to the nitrile 10. G. Sekar of the Indian Institute of Technology Madras effected... 

Klapper, L., McKnight, D.M., Eulton, J.R., Blunt- Harris, E.L., Nevin, K.P., Lovely, D.R., and Hatcher, P.G. (2002). Eulvic acid oxidation state detection using fluorescence spectroscopy. Environ. Sci. TechnoL, 36, 3170-3175. 

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