Carboxylic acid general rules

Hydrolysis of aspirin in H2 0 leads to no incorporation of into the product salicylic acid, ruling out the anhydride as an intermediate and thereby excluding mechanism 1. The general acid catalysis of mechanism III can be ruled out on the basis of failure of other nucleophiles to show evidence for general acid catalysis by the neighboring carboxylic acid group. Because there is no reason to believe hydroxide should be special in this way, mechanism III is eliminated. Thus, mechanism II, general base catalysis of hydroxide-ion attack, is believed to be the correct description of the hydrolysis of aspirin. 

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

Finally, even if these criteria are satisfied, there remains the question of whether the product will adhere to form a film or just precipitate homogeneously in the solution. This is the most difficult criterion to answer a priori. The hydroxide and/or oxy groups present on many substrates in aqueous solutions are likely to be quite different in a nonaqueous solvent (depending on whether hydroxide groups are present or not). Another factor that could conceivably explain the general lack of film formation in many organic solvents is the lower Hamaker constant of water compared with many other liquids this means that the interaction between a particle in the solvent and a solid surface will be somewhat more in water than in most other liquids (see Chapter 1, van der Waals forces). From the author s own experience, although slow precipitation can be readily accomplished from nonaqueous solutions, film formation appears to be the exception rather than the rule. The few examples described in the literature are confined to carboxylic acid solvents (see later). 

However, a careful study of the experimental data has led to some general trends. For instance, the nature of the final products depends heavily on the alkali cations used in the starting compounds sodium and lithium phenoxides reacting under similar experimental conditions yield the related salicylates as major products [18] (Scheme 5.1), whereas potassium, rubidium, and cesium phenoxides yield mixtures of 2-hydroxy-benzoic acid and 4-hydroxy-benzoic acid [1] (Scheme 5.2). As a rule of thumb, the yield of p-hydroxybenzoic acid generally increases with the increasing ionic radius of the alkali metal. Both, temperature and C02-pressure were also reported to be paramount in the selectivity of the carboxylation ... 

The heteroatoms most commonly encountered by the organic chemist are oxygen, nitrogen and sulphur. The position of absorption of protons attached to these atoms is not normally sufficiently reliable for interpretative purposes, although there are exceptions to this general rule (e.g. carboxylic acids, enols,... 

The nature and amount of the amine used for acid deprotonation determines the reaction yield. In most cases, dienediolates of unsaturated carboxylic acids can be generated, without Barbier s reduction or Michael adduct formation, by deprotonation of the corresponding acid with butyllithium in the presence of a catalytic amount of amine198. This renders dienediolates compatible with a large number of functional groups, as happens with nitriles where self-condensation is minimized under these conditions. Unfortunately, this cannot be considered a general rule and it is convenient to optimize the amine and its amount for each acid and nitrile. 

What bases are used to deprotonate a carboxylic acid As we learned in Section 2.3, equilibrium favors the products of an acid-base reaction when the weaker base and acid are formed. Because a weaker acid has a higher pK, the following general rule results ... 

The effect of buffer concentration. For solutes containing a carboxylic acid moiety, the general rule appears to be that the lower the buffer... 

In order to construct crystals of this required structure type, we applied some empirical rules of packing. We avoided the use of carboxylic acids or primary amides, since molecules containing these functional groups generally pack in centrosymmetric or Mfifi / -centrosymmetric structures. Instead, we selected ester moieties as X and Y, because in many crystals bearing these functional groups an attractive interaction between carbonyls and phenyls of adjacent molecules has been observed which would juxtapose the double bonds, in our case, at the correct distance and in the required geometry (Scheme 3). ° Non-equivalence between the two reactive sites was... 

The thiolates, though less sensitive to basicity, are more reactive than oxygen anions over the total accessible range of basicity, but intersect the amine line at ca. pA 12. Other reactive nucleophiles which do not fall in the amine, thiolate, or oxygen anion categories are fluoride, thiosulfate, nitrite, azide, and sulfite. Halides other than fluoride, and also thiocyanate, nitrate, sulfate, and thiourea have no reactivity towards p-nitrophenyl acetate (Jencks and Carriuolo, 1960a). The total lack of reactivity of thiocyanate, iodide, bromide, and thiourea, all very polarizable nucleophiles which are reactive to sp carbon, rules out any possibility that polarizability is at all important in nucleophilic reactions at the carbonyl carbon. In general, the order of nucleophilic reactivity to p-nitrophenyl acetate correlates well with nucleophilic reactivity to other carboxylic acid derivatives (see later). Nitrite, however, shows... 

Choice of solvent. The solvent cannot be selected on the basis of rules or theoretical considerations but must be experimentally determined. There are certain theoretical considerations which serve as a general guide for example, it is known that naphthalene, CioHs, is insoluble in water, H2O, but soluble in benzene, CeHe. From similar studies the general rule is drawn that a solid is best dissolved in a liquid which it resembles in chemical composition and structure. An organic carboxylic acid RCOOH is expected to dissolve in water since it contains the hydroxyl group, OH but if... 

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