TY - JOUR
T1 - Substituents on quinone methides strongly modulate formation and stability of their nucleophilic adducts
AU - Weinert, Emily E.
AU - Dondi, Ruggero
AU - Colloredo-Melz, Stefano
AU - Frankenfield, Kristen N.
AU - Mitchell, Charles H.
AU - Freccero, Mauro
AU - Rokita, Steven E.
PY - 2006/9/13
Y1 - 2006/9/13
N2 - Electronic perturbation of quinone methides (QM) greatly influences their stability and in turn alters the kinetics and product profile of QM reaction with deoxynucleosides. Consistent with the electron-deficient nature of this reactive intermediate, electron-donating substituents are stabilizing and electron-withdrawing substituents are destabilizing. For example, a dC N3-QM adduct is made stable over the course of observation (7 days) by the presence of an electron-withdrawing ester group that inhibits QM regeneration. Conversely, a related adduct with an electron-donating methyl group is very labile and regenerates its QM with a half-life of approximately 5 h. The generality of these effects is demonstrated with a series of alternative quinone methide precursors (QMP) containing a variety of substituents attached at different positions with respect to the exocyclic methylene. The rates of nucleophilic addition to substituted QMs measured by laser flash photolysis similarly span 5 orders of magnitude with electron-rich species reacting most slowly and electron-deficient species reacting most quickly. The reversibility of QM reaction can now be predictably adjusted for any desired application.
AB - Electronic perturbation of quinone methides (QM) greatly influences their stability and in turn alters the kinetics and product profile of QM reaction with deoxynucleosides. Consistent with the electron-deficient nature of this reactive intermediate, electron-donating substituents are stabilizing and electron-withdrawing substituents are destabilizing. For example, a dC N3-QM adduct is made stable over the course of observation (7 days) by the presence of an electron-withdrawing ester group that inhibits QM regeneration. Conversely, a related adduct with an electron-donating methyl group is very labile and regenerates its QM with a half-life of approximately 5 h. The generality of these effects is demonstrated with a series of alternative quinone methide precursors (QMP) containing a variety of substituents attached at different positions with respect to the exocyclic methylene. The rates of nucleophilic addition to substituted QMs measured by laser flash photolysis similarly span 5 orders of magnitude with electron-rich species reacting most slowly and electron-deficient species reacting most quickly. The reversibility of QM reaction can now be predictably adjusted for any desired application.
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U2 - 10.1021/ja062948k
DO - 10.1021/ja062948k
M3 - Article
C2 - 16953635
AN - SCOPUS:33748509102
SN - 0002-7863
VL - 128
SP - 11940
EP - 11947
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 36
ER -