Page 895 - Advanced Organic Chemistry Part A - Structure and Mechanisms, 5th ed (2007) - Carey _ Sundberg

the endo and exo TSs in D-A reactions. Substituted diazoalkanes, for example, can 879
add to unsymmetrical dipolarophiles to give two diastereomers.
SECTION 10.3
H Ph 1,3-Dipolar
– + H CH 3 Ph N N H N N Cycloaddition Reactions
PhCH N N + CH 3 +
CH 3 O 2 C CO 2 CH 3 CH 3
CH 3 O 2 C CO 2 CH 3 CH 3 O 2 C CO 2 CH 3
Ref. 120

For unsymmetrical dipolarophiles, two regioisomeric products are also possible.
The prediction and interpretation of the stereo- and regioselectivity of 1,3-DPCA
reactions have been of ongoing interest. The issues are the same as in the D-A
reaction. The reactions are usually under kinetic control, so TS energy is the controlling
factor. As the reactants come together, charge transfer and polarization occur, with
one reactant donating electron density to the other. As the TS is reached, the degree
of bond formation and electron delocalization are important. The TS can be charac-
terized by the extent of orbital interaction, charge transfer, and the degree of bond
formation. 121 Reactant conformation may also be a factor in distinguishing between
exo and endo TSs. For any given reaction, computational comparison of TS energies
can be informative, but there is also a need for qualitative understanding of the factors
that contribute to TS energy and therefore to regio- and stereocontrol.
The polarity of the common dipolarophiles can be recognized from the nature of
the substituent.

δ + δ –
EWG δ – ERG δ +

When both the 1,3-dipole and the dipole are unsymmetrical, there are two possible
orientations for addition. Both steric and electronic factors play a role in determining
the regioselectivity of the addition. The most generally satisfactory interpretation of the
regiochemistry of 1,3-DPCA is based on frontier orbital concepts. 122 As with the D-A
reaction, the most favorable orientation is the one that gives the strongest interaction
between the frontier orbitals of the 1,3-dipole and the dipolarophile. Most 1,3-DPCA
are of the type in which the frontier orbitals are the LUMO of the dipolarophile and
the HOMO of the 1,3-dipole. There are a number of systems in which the relationship
is reversed, as well as some in which the two possible HOMO-LUMO interactions are
of comparable magnitude.
The analysis of the regioselectivity of a 1,3-dipolar cycloaddition by FMO theory
requires information about the energy and atomic coefficients of the frontier orbitals
of the 1,3-dipole and the dipolarophile. Most of the more common 1,3-dipoles have
been examined using CNDO/2 calculations. 122b Figure 10.14 gives estimates of the
energies of the HOMO and LUMO orbitals of some representative 1,3-dipoles. By
using these orbital coefficients and calculating or estimating the relative energies

120
R. Huisgen and P. Eberhard, Tetrahedron Lett., 4343 (1971).
121 P. Merino, J. Revuelta, T. T. Tejero, U. Chiacchio, A. Rescifina, and G. Romeo, Tetrahedron, 59, 3581
(2003).
122
(a) R. Sustmann and H. Trill, Angew. Chem. Int. Ed. Engl., 11, 838 (1972); (b) K. N. Houk, J. Sims,
B. E. Duke, Jr., R. W. Strozier, and J. K. George, J. Am. Chem. Soc., 95, 7287 (1973); (c) R. Sustmann,
Pure Appl. Chem., 40, 569 (1974); (d) I. Fleming, Frontier Orbitals and Organic Chemical Reactions,
Wiley, New York, 1977; (e) K. N. Houk, in Pericyclic Reactions, Vol. II, A. P. Marchand and R. E. Lehr,
eds., Academic Press, New York, 1977, pp. 181–271; (f) K. N. Houk, Top. Curr. Chem., 79, 1 (1979).