Baldwin's Rules - Department of Medicinal Chemistry

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Table 14. Activation, Reaction and Intrinsic Energies
(kcal/mol) for the Parent 4-exo- and 5-endo-dig Radical
Digonal Cyclizations at the B3LYP/6-31+G(d,p) and
M05-2X/6-31+G(d,p) Levels of Theory a
a
The M05-2X data are given in parentheses and the ring-closing bond is
shown in red.
Table 15. Transition State Geometries, NICS (0) Values, and
LUMO Plots for 4-exo/5-endo Carbanionic Cyclizations for the
Me-Substituted Alkyne Calculated at the M05-2X/6-31+G** Level a
a Bond lengths given in Å. Activation, reaction, and intrinsic energies
(kcal/mol) for the parent 4-exo- and 5-endo-dig anionic cyclizations at the
B3LYP/6-31+G(d,p) and M05-2X/6-31+G(d,p) levels of theory. M05-2X
data are given in parentheses. Ring-closing bonds are shown in red.
comes from the thermodynamic component as aromaticity of the
benzothiophene moiety provides an additional 12 16 kcal/mol
Figure 15. Conflict between unfavorable secondary orbital interactions
(crossed red arrow) and in-plane aromaticity in anionic 5-endo-dig cyclizations.
stabilization to the product. Thus, this example provides the first
demonstration of aromatic stabilization being a driving force for
5-endo-dig radical cyclizations. Longer C S bonds also help in
alleviating the geometric requirements in achieving the required
attack angle.
Table 16. Literature Examples of 4-exo/5-endo-dig Anionic
Closure with Respect to the Environment of the Anionic Center a
a x marks denote gaps in the literature. Motif structures are given in Scheme 1.
Motifs B and G are unknown, and D and E do not apply to anionic closures.
3.2.2. Anionic Cyclizations (Table 16). Recent computational
analysis 24 revealed that, unlike the smaller (3-exo/4-endo) and larger
(5-exo/6-endo) analogs, the activation barriers of 4-exo- and 5-endodig
anionic closure of the parent systems are quite similar
(Table 14). This seemingly irregular trend has been suggested
to stem not purely from stereoelectronic factors, but rather
originate from their interplay with thermodynamic contributions
to the activation barrier. 24 When thermodynamic driving
forces for the two cyclizations are similar (both products are
either strained (3-exo/4-endo) or not (5-exo/6-endo), there is
a clear kinetic preference for the exo path. Only for the special
case where the exo-product is much more strained than the
endo product (the 4-exo/5-endo pair) and the endo cyclization
is much more exothermic, the exo/endo kinetic competition becomes
relatively close. 93
Q dx.doi.org/10.1021/cr200164y |Chem. Rev. XXXX, XXX, 000–000