THE IONIZATION OF MORPHINE, HYDROXY AMPHETAMINE AND (+)‐TUBOCURARINE CHLORIDE AND A NEW METHOD FOR CALCULATING ZWITTERION CONSTANTS

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Abstract
An improved method for estimating the zwitterion constants of phenolic amines is described which involves the exploratory least‐squares fit of absorbance (at a suitable wavelength) to pH, starting with estimates of pK1 and pK2 obtained electrometrically. With the method it is possible to see that hydroxyamphetamine (α‐methyltyramine) has a higher zwitterion constant than tyramine and the zwitterion constants of both compounds are lower at 37°C than at 25°C. The zwitterion constant of morphine is not reduced by raising the temperature from 25° to 37°C and the effect of temperature is much greater in compounds with a primary or secondary amino group than with those containing a tertiary amino group. Some zwitterions may be stabilized by hydration and their formation will be reduced by a rise in temperature which will break up water structure. From electrometric titrations with (+)‐tubocurarine chloride in 0.1 m NaCl estimates of pK1, pK2 and pK3 were 7.6, 8.65 and 9.65 at 25°C and 7.4, 8.6 and 9.7 at 37°C, compared with 7.8, 8.85 and 9.75 given by Perrin (1980). However, the effects of pH on absorbance show that the phenolic groups lose a proton before the ammonium group so there is extensive zwitterion formation which is probably greater at 25° than at 37°C. The p‐phenolic group (position 13) probably ionizes first with the phenate form stabilized by hydration involving water molecules and the protonated form of the (1‐) ammonium group.
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