High- and Low-Potential Flavin Mimics. 2. 3,7,10-Trimethyl-(1H,3H,5H,7H,9H,10H)-pyrimidopteridine-2,4,6,8-tetrone Dianion Reduction of Carbonyl, Nicotinamides, and Alkyl Disulfide Functional Groups

Article abstract of DOI:10.1021/ja00348a059

3,7,10-Trimethyl-(3H,7H,9H,10H)-pyrimido<5,4-g>pteridine-2,4,6,8-tetrone (PPT_ox) and its conjugate base (PPT_ox^-) undergo two-electron reduction to yield 3,7,10-trimethyl-(1H,3H,5H,7H,9H,10H)-pyrimido<5,4-g>pteridine-2,4,6,8-tetrone (PPTH2) and its dianion (PPT^2-) (Scheme I).The two-electron redox potential E⁰' is 150 mV more negative than that of the corresponding 3-methyllumiflavin (Fl_ox)/1,5-dihydro-3-methyllumiflavin (FlH2 + FlH^-) couple.Reductive alkylation of PPTH2 with acetaldehyde (Scheme II) provides the N⁵-ethyl derivative of PPTH2 (N⁵-EtPPTH2) which is an analogue of the well studied 1,5-dihydro-N⁵-ethyl-3-methyllumiflavin (N⁵-EtFlH).As in the instance of N⁵-EtFlH, N⁵-EtPPTH2 can undergo stepwise oxidation to the thermodynamically stable N⁵-EtPPT^-. radical (analogue of N⁵-EtFl^.) and hence to the two-electron oxidized species N⁵-EtPPT_ox (Scheme II).The pK_a for the pseidobase formation via reaction of N⁵-EtPPT_ox with H2O (7.34) is compared to the similar pK_a (4.00) for the reaction of N⁵-EtFl_ox⁺ with H2O.The species PPT_ox^- (like Fl_ox) is not reduced (H2O solvent) with NaCNBH3.However, reduction of a solution of PPT_ox^- containing formaldehyde with NaCNBH3 yields N⁵-MePPT_ox and the radical N⁵-MePPT^-. on admittance of O2.The mechanism (Scheme III) involves the initial formation of the N¹-carbinolamine of PPT_ox^- which when reduced is subject to reductive alkylation at N⁵, as in the case of reductive alkylation of PPTH2.The reaction of PPTH2 with formaldehyde has been studied in detail.The reaction resembles, in important details, that for the reaction of FlH2 with formaldehyde.An initial first-order burst in the formation of PPT_ox^- is associated with the competitive reduction of formaldehyde by PPT^2- and the formation of the N⁵-imine of PPT^2- (eq 5; Scheme IV).The latter does not apparently revert readily to carbinolamine, due to its electronic stabilization (structures A, B, C, and D).The N⁵-imine of PPT^2- is trapped in further reactions to produce compounds with more positive potentials than that for the PPT_ox^-/PPTH2 couple (possible structures as E, F, etc.).The increase in the rate constant of specific acid catalyzed reduction of formaldehyde by PPT^2- (k = 3.3x10⁶ M^-2 s^-1) over the like constant with FlH^- (k = 2.3x10⁴ M^-2 s^-1) is related to the difference in the two-electron reduction potential for the two (148 mV) by the free energy relationship 67 mV/Δ log k.The predicted free energy relationship for a series of 1,5-dihydroflavins of varying potentials carrying out reduction of a substrate by two-electron transfer would be 60 mV/Δ log k.Thus, toward formaldehyde, PPT^2- exhibits the reactivity of a low-potential FlH^- molecule.The reaction of PPTH2_T (=PPTH2 + PPT^- + PPT^2-) with m-hydroxybenzaldehyde was studied at pH 5.00 only.In preparative experiments, it was shown that m-hydroxybenzaldehyde was reduced to m-cresol and a trace of m-hydroxybenzyl ...