Large steric effect in the substitution reaction of amines with phosphoimidazolide-activated nucleosides.
Aliphatic amines react with phosphoimidazolide-activated derivatives of guanosine and cytidine (ImpN) by replacing the imidazole group.  The kinetics of reaction of guanosine 5'-phospho-2-methylimidazolide (2-MeImpG) with glycine ethyl ester, glycinamide, 2-methoxyethylamine, n-butylamine, morpholine, dimethylamine (Me2NH), ethylmethylamine (EtNHMe), diethylamine (Et2NH), pyrrolidine, and piperidine were determined in water at 37 degrees C.  With primary amines, a plot of the logarithm of the rate constant for attack by the amine on the protonated substrate, log kSH(A), versus the pKa of the amine exhibits a good linear correlation with a Bronsted slope, beta nuc = 0.48.  Most of the secondary amines tested react with slightly higher reactivity than primary amines of similar pKa.  Interestingly, some secondary amines show substantially lower reactivity than might be expected:  EtNHMe reacts about eight times, and Et2NH at least 100 times, more slowly than Me2NH although all three amines are of similar basicity.  For comparison, the kinetics of reaction of guanosine 5'-phosphoimidazolide (ImpG) and cytidine 5'-phosphoimidazolide (ImpC) were determined with Me2NH, EtNHMe, and Et2NH, and similar results were obtained.  These results establish that the increased steric hindrance observed with the successive addition of ethyl groups are not due to any special steric requirements imposed by the guanosine or the methyl on the 2-methylimidazole leaving group of 2-MeImpG.  It is concluded that addition of ethyl and, perhaps, groups larger than ethyl dramatically increases the kinetic barrier for addition of aliphatic secondary amines to the P-N bond of ImpN.  This study supports the observation that the primary amino groups on the natural polyamines are at least 2 orders of magnitude more reactive than the secondary amino groups in the reaction with ImpN.
Kanavarioti
A
A
Department of Chemistry and Biochemistry, University of California, Santa Cruz 95064, USA.
Stronach
M W
MW
Ketner
R J
RJ
Hurley
T B
TB
D000588:Amines / Q000737:chemistry*; D055598:Chemical Phenomena; D002621:Chemistry; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry; D007700:Kinetics; D009705:Nucleosides / Q000737:chemistry*
D000588:Amines; D009705:Nucleosides; C025339:guanosine 5'-phosphoimidazolide; C036896:guanosine 5'-phospho-2-methylimidazolide; D006157:Guanosine Monophosphate