Catalysis of Vitamin A Aldehyde Isomerization by Primary and Secondary Amines

Article abstract of DOI:10.1021/ja00328a037

Model studies were conducted to quantitatively assess the role of Schiff base formation in catalyzing thermal isomerizations of vitamin A aldehydes (retinaldehyde), processes that are known to be critical for vertebrate vision and proton pumping in certain halophilic bacteria.Schiff base formation by itself, between vitamin A aldehydes and either saturated or aromatic amines, does not strongly enhance the measured thermal rates of isomerization.However, protonation of the Schiff bases strongly enhances their rates of isomerization; at 65 deg C the first-order rates of thermal isomerization of 11-cis-retinal, the n-butylamine Schiff base, and the aniline Schiff base are 2.4*10^-6, 8.0*10^-6, and 2.8*10^-6 s^-1, respectively.At 25 deg C the HCl-catalyzed rates of isomerization of the n-butylamine Schiff bases of 11-cis-, 13-cis-, and 9-cis-retinal are 2*10^-2, 3*10^-2, and 9.4*10^-4 s^-1, respectively.However, the rates of these isomerization reactions appear to be dependent on the strength of the conjugate base because base catalysis is probably required.Trifluoroacetic acid proved to be a much weaker catalyst than HCl.Under conditions of approximately equal protonation, the first-order rates of isomerization of the n-butylamine and aniline Schiff bases of 11-cis-retinal are 2.6*10^-6 and 7.9*10^-4 s^-1 at 25 deg C.This result is most easily understood in terms of the greater nucleophilicity of chloride vs. trifluoroacetate.Adding nucleophilic bases to the protonated primary amine Schiff bases to enhance the rate of isomerization is not possible because the deprotonation of the Schiff base renders base catalysis ineffective.However, Schiff bases formed with secondary amines, such as piperidine, can obviate this problem because their positive charge cannot be neutralized by proton transfer.It is shown here that piperidine also catalyzes the isomerization of vitamin A aldehydes with a pseudo-first-order rate constant of k=4.1*10^-5 s^-1 at 37 deg C, but here the rate-limiting step is Schiff base formation itself, rather than the isomerization reactions.The model studies reported here suggest that the physiological mechanism of vitamin A aldehyde isomerization will involve positively charged Schiff base formation followed by nucleophilic attack on the relevant carbon-carbon double bond.The fact that biological molecules, such as reduced flavins and phosphatidylethanolamine (PE), catalyze the isomerizations of the vitamin A aldehydes is in accord with this view.