Mensah Mary, Amepetey Evans Elikem, Tia Richard, Adei Evans
Department of Chemistry, Kwame Nkrumah University of Science and Technology, PMB University Post Office, Kumasi, Ghana.
Springerplus. 2016 Dec 5;5(1):2072. doi: 10.1186/s40064-016-3758-0. eCollection 2016.
1,3-Dipolar [3 + 2]-cycloaddition of nitrones to the carbon-carbon double bonds of methylenecyclopropanes yields a mixture of regioisomeric 4- and 5-isoxazolidines. The mechanisms of the reactions of ,,-trisubstituted nitrones with ring acceptor substituted dimethyl methylenecyclopropanes-1,2-dicarboxylate and aryl methylidene cyclopropanes-1,1-dicarboxylate have been investigated with the Becke 3-Parameter Lee-Yang-Par exchange-correlation functional, a Hartree-Fock DFT hybrid functional, to delineate the factors responsible for the regioselectivity of these class of reactions.
The energetics of the reaction of the phenyl-substituted nitrone with unsubstituted methylenecyclopropane indicate that the formation of the 5-spirocyclopropane is favored over the 4-spirocyclopropane kinetically and thermodynamically. However, the energetics of the reaction of the same phenyl nitrone with vicinal ester (-COCH)-substituted methylenecyclopropane show an inversion in the regioselectivity favoring the formation of the 4-regioisomer over the 5-regioisomer. For the reactions of ,,-trisubstituted nitrone with vicinal ester (-COCH)-substituted methylenecyclopropane (-R=H, -R=Ph and -R=CH and -R=COCH) and geminal ester (-COCH)-substituted methylenecyclopropane (R=H, R=H; R=OCH, R=CH; and R=H, R=Cl), the energetics indicate that the 5-spirocyclopropane is favored over the 4-spirocyclopropane. The calculations also indicate that electron-donating groups increase regioselectivity of the 5-regioisomers over the 4-regioisomers.
The regioselectivity of these reactions is determined by both electronic and steric factors. The pathways with the lower activation barrier leads to the more stable regioisomer in all cases, implying that the pathways that are kinetically favored are also thermodynamically favored. However, it is also clear from the energetics that these reactions are not reversible and are therefore under kinetic control. Therefore the selectivity of the reactions is governed solely by the difference in activation barriers leading to the two isomers and not in any way by the thermodynamic stability of the isomers formed.
硝酮与亚甲基环丙烷的碳 - 碳双键发生的1,3 - 偶极[3 + 2]环加成反应会生成区域异构体4 - 和5 - 异恶唑烷的混合物。使用Becke三参数Lee - Yang - Par交换相关泛函（一种Hartree - Fock DFT混合泛函）研究了α,β,γ - 三取代硝酮与环受体取代的二甲基亚甲基环丙烷 - 1,2 - 二羧酸酯和芳基亚甲基环丙烷 - 1,1 - 二羧酸酯的反应机制，以确定影响这类反应区域选择性的因素。
苯基取代的硝酮与未取代的亚甲基环丙烷反应的能量学表明，在动力学和热力学上，5 - 螺环丙烷的形成比4 - 螺环丙烷更有利。然而，相同的苯基硝酮与邻位酯（ - COCH）取代的亚甲基环丙烷反应的能量学显示区域选择性发生反转，有利于4 - 区域异构体而非5 - 区域异构体的形成。对于α,β,γ - 三取代硝酮与邻位酯（ - COCH）取代的亚甲基环丙烷（ - R = H， - R = Ph和 - R = CH以及 - R = COCH）和偕二酯（ - COCH）取代的亚甲基环丙烷（R = H，R = H；R = OCH，R = CH；以及R = H，R = Cl）的反应，能量学表明5 - 螺环丙烷比4 - 螺环丙烷更有利。计算还表明，供电子基团会增加5 - 区域异构体相对于4 - 区域异构体的区域选择性。
这些反应的区域选择性由电子因素和空间因素共同决定。在所有情况下，具有较低活化能垒的途径会生成更稳定的区域异构体，这意味着动力学上有利的途径在热力学上也是有利的。然而，从能量学上也很清楚，这些反应是不可逆的，因此处于动力学控制之下。因此，反应的选择性仅由导致两种异构体的活化能垒差异决定，而不以任何方式由所形成异构体的热力学稳定性决定。
