Problematic Carboxylic Acids

The least problematic issues are UV spectral changes as a function of different solvents between the reference and the test sample. Solvent effects on UV spectra in solvents of decreased dielectric constant compared with water parallel solvent effects on apparent pKa. The changes are most marked for acids, for example, leading to a numerical increase of up to two pKa units - an apparent decrease in the acidity of the carboxylic acid. Effects on bases are considerably less. The apparent pKa of a base in a reduced dielectric constant solvent might be up to about half a pKa unit numerically lower (less basic). The UV spectra of neutral compounds... 

To summarize the amides are most suitable for the formation, by ortholithiation, of condensed heterocycles and polycyclic aromatics (in which subsequent rings are formed by intramolecular attack on the amide group). In other cases the removal of the amide group may be problematic, though if carboxylic acids, aldehydes or hydroxymethyl-substituted compounds are required, alternative amide substituents may be used. 

Dithiin, 1,4-benzodioxin, and its 2-substituted derivatives can be readly deprotonated and trapped with electrophiles although the reaction is more problematic with 1,4-dioxin. Oxanthrene and phenoxathiin are cleaved with lithium <1996CHEC-II(6)447>. A more recent example deals with the metallation at C-3 of the 1,4-benzodioxane 60 bearing a carboxylic acid function at C-2, with lithium diisopropylamide (EDA) and subsequent quench with iodomethane. The corresponding 3-methylated benzodioxane 61 was isolated in 70% yield (Equation 6) <2000EJM663>. 

In an effort to explore the chemistry of pyrrolodiazines and their quatemized salts (see Section 6.2.2.2), Alvarez-Builla and co-workers prepared a series of pyrrolo[l,2-c]pyrimidines via methodology developed in their laboratory <99JOC7788>. Cyclocondensation of tosylmethyl isocyanide with substituted pyrrole-2-carboxaldehydes 17 produced pyrimidine derivatives 18 sifter removal of the tosyl group. The key to this procedure was the use of tosylmethyl isocyanide, which provided a relatively easily removed tosyl group in comparison to the more problematic decarboxylation of a carboxylic acid functionality. 

In their study on the automation of the derivatization reaction of carboxylic acids, Wolf and Korf (34) chose bromomethylmethoxycoumarin (Br-MMC) as a label because of its commercial availability. The automation of this reaction is problematic, because elevated temperatures are required in the manual procedures and the reaction had to take place in an aprotic environment. The addition of a solid salt also complicates the procedure. They describe a solution to this problem using a suspension of potassium carbonate and appropriate reagent concentrations. The samples were detected by a fluorescence detector equipped with a 5-ju.l cell, using an excitation wavelength of 325 nm and a cutoff filter of 398 nm. 

One of the most common strategies for preparation of carboxylic acid derivatives is the acylation of nucleophiles of general formula RXH (X = NR, O, S). If the right reaction conditions are chosen and if the product is stable these reactions usually proceed swiftly and in high yield. Some carboxylic acids and nucleophiles, however, do not react smoothly or lead to unexpected results. The following sections cover a selection of representative examples of problematic starting materials. 

Panke et al. (2003) also demonstrated enhanced reaction control, with respect to the temperature-sensitive synthesis of 2-methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxylic acid 219, a key intermediate in the synthesis of the lifestyle drug Sildenafil (220) (Scheme 64). When performing the nitration of 2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid 219 under adiabatic conditions, with a dilution of 6.01kg 1), Dale et al. (2000) observed a temperature rise of 42 °C (from 50 to 92 °C) upon addition of the nitrating solution. As Scheme 63 illustrates, this proved problematic as at 100 °C decomposition of the product 219 was observed and in order to reduce thermal decomposition of pyrazole 219, and increase process safety, the authors investigated addition of the nitrating solution in three aliquots, which resulted in a reduced reaction temperature of 71 °C and an increase in chemoselectivity unfortunately, the reaction time was increased from 8 to 10 h. 

The use of oxoammonium ions such as those derived from TEMPO in combination with inexpensive, safe, and easy-to-handle terminal oxidants in the conversion of alcohols into aldehydes, ketones, and carboxylic acids is a significant example of how it is possible to develop safer and greener chemistry, by avoiding the use of environmentally-unfriendly or toxic metals. However, separation of the products from TEMPO can be problematic, especially when the reactions are run on... 

The most common reagents for lysine modification are NHS-esters, which react with amines at rates that are significantly greater than background hydrolysis. Fig. 2a (13). These reagents are most commonly prepared from carboxylic acids and isolated before exposure to the protein substrate. Because of the popularity of this method, dozens of premade NHS-esters are now commercially available. In cases where aqueous solubility is problematic, sulfonated NHS-esters can be used. Because virtually all proteins have many lysine residues on their surface, this reaction affords the most reliable and general method... 

Analysis of pH-independent rates of hydrolysis of substituted 2-methoxy-methoxy benzoic acids and salicyl-substituted versions of VII gave for the phenol Pi =0.89 and 0.93, respectively. These values correspond to a /fig value of 0.4, which is commonly observed with many glycosidase-catalysed hydrolyses of aryl glycosides. The low values for the carboxylic acid p2 (0.02 and 0.2) are more problematic, as they should be the same as the Bronsted a perhaps a strong hydrogen bond in the ground state is part of the cause. 

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