Proton acids, weak hydrobromide

Bis-(4-acetoxyphenyl)methyl]pyridine N-oxide and ethyldiisopropylamine hydrobromide as weak proton acid in acetic anhydride refluxed vigorously for 1 hr. -> 3-acetoxy-10-(4-acetoxyphenyl)-pyrido[l,2-a]indole. Y 81%. - Instead of acetic anhydride, 1,1,2,2-tetrachlorethane may be used as medium. J. Sdinekenburger, Ardi. Pharm. 306, 360 (1973). 

When amino acid ester prodrugs of acetaminophen were prepared (Kovach et al., 1975 Pitman, 1976), the hydrobromide salt of the glycine ester showed enhanced solubility in water, but the hydrochloride salt of th -aspartic acid ester exhibited a solubility lower than that of the parent compound. The enhanced solubility resulted from the formation of a salt, while the parent drug is a weakly acidic phenol and behaves as essentially a neutral molecule in solution. The reduced solubility in the case of th0-aspartic acid ester resulted from ionization of the terminal carboxylic acid, which, with the protonated amine, gives a zwitterionic compound. The zwitterion also behaved as a molecule with an overall neutral character, as is commonly observed with zwitterion behavior in aqueous media, but its larger size resulted in a further reduced solubility. 

Figure 12.25 shows how acetals can be brominated electrophihcally because of the (weakly) acidic reaction conditions. Proper acidity and electrophihcity is ensured by the use of pyri-dinium tribromide (B). This reagent is produced from pyridinium hydrobromide and one equivalent of bromine. Pyridinium tribromide is acidic enough to cleave the acetal A into the enol ether G. This cleavage succeeds by way of an El elimination like the one encountered in Figure 9.32 as an enol ether synthesis. The enol ether G reacts with the tribromide ion via the bromine-containing oxocarbenium ion H and the protonated acetal D to form the finally isolated neutral bromoacetal C. (The reaction can be conducted despite the unfavorable equilibrium between the acetal A and the enol ether G, since G continuously reacts and is thus eliminated from the equilibrium.)... 

This type of behavior is not limited to amine hydrochlorides, and amine hydrobromides and hydrothiocyanates undergo similar reactions. Some of the reactions of amine hydrochlorides and hydrothiocyanates are useful in the preparation of coordination compounds containing the amines. The important characteristic is that ammonia or a protonated amine is a conjugate acid of a weak base and is able, therefore, to react as an acid. 

---

See also in sourсe #XX -- [ , ]

---