Baldwin's Rules - Department of Medicinal Chemistry

Chemical Reviews REVIEW
Scheme 6. 3-exo-dig Cyclizations of Enolates and Propargylic
Alcohols
Table 6. Activation, Reaction, and Intrinsic Energies
(kcal/mol) for the Parent 3-exo- and 4-endo-dig Anionic
Digonal Cyclizations at the B3LYP/6-31+G(d,p) and
M05-2X/6-31+G(d,p) Levels of Theory b
a The ring-opening reaction is barrierless. b The M05-2X data are given
in parentheses. Ring-closing bond shown in red.
Baldwin rules rather than difficulties in trapping the cyclobutenyl
reactiveintermediatebeforeitundergoes ring-opening or another
unproductive reaction. On the basis of the >20 kcal/mol difference
in activation barriers between 3-exo and 4-endo closures, the
absence of nucleophilic 4-endo-dig cyclizations is not surprising,
even though the parent 4-endo-dig cyclization is about ∼7 kcal/
mol more exothermic than its 3-exo-dig counterpart (Table 6,
Figure 13).
Anion-stabilizing substituents at the terminal alkyne carbon
slighty increase the calculated kinetic preference for the 3-exo-dig
closure (Table 7).
Although only computational data are available for this class of
cyclizations, they provide sufficient background for illustrating the
keytrends.Theremarkablyhighactivationenergy(∼30 kcal/mol)
for the >10 kcal/mol exothermic 4-endo-dig cyclization of parent
but-3-ynyl carbanion 67 was attributed to homoantiaromaticity 24,68
and cancellation of the stabilizing n Nu f π* interaction for the acute
trajectory which brings the nucleophile at the node of the
alkyne in-plane π*-orbital. The antiaromatic character of the
4-endo TS is illustrated by the positive NICS 69 value (Table 7)
and is consistent with its 4n-electron count (Figure 12).
Table 7. Transition State Geometries, NICS (0) Values,
and LUMO Plots for 3-exo/4-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 3-exo- and 4-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.
Figure 12. Homoantiaromaticity in an anionic 4-endo-dig transition state.
Even for the formation of strained cycles, all carbanionic cyclizations
are exothermic and effectively irreversible due to the conversion
of a weaker bond into a stronger bond (π-bond f σ-bond)
and the concomitant transformation of an alkyl anion into a more
stable vinyl anion. This is true even for the formation of strained
3-exo and 4-endo products.
In contrast, the analogous cyclizations of the parent N- and
O-centered anions transform a heteroatom-centered anion into a
K dx.doi.org/10.1021/cr200164y |Chem. Rev. XXXX, XXX, 000–000