The nucleophilic substitution reactions on substituted
arylcyclopropane cation radicals were studied by a
combination of methods including product studies, time-resolved laser
flash photolysis, kinetic isotope effects, and
quantum chemical calculations. The reactions were found to proceed
stereospecifically with inversion of configuration,
with high regioselectivity for nucleophilic attack at the more
substituted carbon atom, and with very small steric
effects. Electronic effects on the nucleophilic substitution
regiochemistry and the rate constants were found to be
substantial for substituents on the cyclopropane moiety and on the aryl
ring.
The use of glutaraldehyde-treated biological tissue in heart valve substitutes is an important option in the treatment of heart valve disease. These devices have limited durability, in part, because of tissue calcification and subsequent tearing of the valve leaflets. Components thought to induce calcification include lipids, cell remnants, and residual glutaraldehyde. We hypothesized that treatment of glutaraldehyde-treated bioprosthetic heart valve material using a short and long chain alcohol (LCA) combination, composed of 5% 1,2-octanediol in an ethanolic buffered solution, would reduce phospholipid content and subsequently lower the propensity of these tissues to calcify in vivo. Phospholipid content of glutaraldehyde-treated porcine valve leaflets and bovine pericardium was found to be 10.1 +/- 4.3 (n = 7) and 3.9 +/- 0.48 (n = 2) microg/mg dry tissue, respectively, which was reduced to 0.041 +/- 0.06 (n = 7) and 0.21 +/- 0.05 (n = 4) microg/mg dry tissue, respectively, after LCA treatment. Calcification potential of the treated tissues was assessed using a rat subcutaneous implant model. After 60 days of implantation, calcium levels were found to be 171 +/- 32 (n = 11) and 83 +/- 70 (n = 12) mg/g dry weight for glutaraldehyde-treated porcine leaflets and bovine pericardium, respectively, whereas prior LCA treatment resulted in reduced calcium levels of 1.1 +/- 0.6 (n = 12) and 0.82 +/- 0.1 (n = 12) mg/g dry weight, respectively. These data, taken together, support the notion that treatment of glutaraldehyde-treated tissue with a short and long chain alcohol combination will reduce both extractable phospholipids and the propensity for in vivo calcification.
The mechanism of photosensitized nucleophilic substitution
reactions on arylcyclopropanes was investigated.
Stereochemical experiments with methanol, water, and cyanide as
nucleophiles showed that the reactions occurred
stereospecifically with complete inversion of configuration at the
carbon atom undergoing substitution. Independent
generation of the arylcyclopropane cation radicals by nanosecond
transient methods showed that they reacted rapidly
with nucleophiles with kinetics that were first-order in both the
cation radical and the nucleophiles. Through a
combination of transient kinetics and steady-state Stern−Volmer
quenching experiments, the reaction of the
phenylcyclopropane cation radical with methanol was kinetically
correlated with the formation of the substitution
product. The reaction of phenylcyclopropane cation radical with a
series of alcohols as nucleophiles showed small
steric effects.
The effects of alkyl substitution on the rates of bimolecular nucleophilic substitution (SN2) reactions at carbon serve as archetypal examples of steric effects in organic chemistry. The large rate reductions for SN2 reactions at tertiary and neopentyl carbon atoms, for example, are cited in even the most elementary organic textbooks. In this communication, we describe several examples of three-electron SN2 reactions that exhibit greatly diminished steric effects and occur with preferential substitution at the more hindered carbon atom, even when it is tertiary or neopentyl.Previous experiments showed that the 1 -cyanonaphthalenesensitized (1-CN) photooxidation of optically active 1,1-diphenyl-2-methylcyclopropane (1) in the presence of methanol leads exclusively to ether 2.2 This result was rationalized by + undergoing nucleophilic substitution by methanol with inversion of configuration at C2. The rate of this reaction shows secondorder kinetics. These results provide compelling evidence for ring-opening by a three-electron SN2 substitution at C2. However,
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