3.1 1,3-Dipolar Cycloaddition
39
to interact, due to more efficient overlap. This is in turn will favour one regioisomer
over the other. This original application of FMO suggested that 5-substituted
heterocycles were favoured in the majority of cases, with the sole exception of highly
electron-withdrawing groups preferentially yielding either regioisomeric mixtures or
4-substituted products [7].
While this technique is commonly used in the literature as a means to predict or
account for NI regioselectivity, it is far from universal and is in no way quantitative.
More recent approaches have emerged employing density functional theory (DFT)
as a tool with which to understand the regioselectivity of NI cycloadditions [10, 11].
The application of concepts such as hard-soft acid-base theory, molecular electron
density theory, relative electrophilicity and Fukui functions within these higher levels
of theory have enabled a much more accurate understanding of NI regioselectivity,
including quantitative predictions in some instances [12, 13].
However, despite these significant advances, regioselectivty in NI cycloadditions
remains difficult to predict or rationalise. While the vast majority of cases of monosubstituted alkenes and alkynes yield the 5-substituted product [14], numerous
exceptions exist to this trend, making the development of a general set of rules
challenging. While FMO [15, 16] and DFT [17, 18] calculations have both aided
in rationalising unexpected results, neither have demonstrated anything close to
absolute accuracy in their prediction methods.
One curious exception to the unpredictable regioselectivity of NI dipolarophiles
is the use of enamines as substrates. These species exhibit exclusive regioselectivity
for the 4-substituted pyrazoline product over the 5-substituted system, apparently
in contrast to the combined steric and electronic influences that direct most other
functional groups to the 5-position [3, 19]. This is discussed in more detail in
Sect. 3.2.8.
It has also been shown that NI regioselectivity can be influenced through the use
of a Lewis acid. Addition of scandium(III) triflate to the reaction mixture shown in
Scheme 3.2 was shown to yield the 4-substituted pyrazole products in a much higher
ratio than in the absence of the additive [20]. Unfortunately, this approach is limited
to substrates with coordinating functional groups, such as carbonyls, adjacent to both
the dipole and dipolarophile.
3.1.2 Rate of Reaction
The rate of reaction of NIs with dipolarophiles can be significantly influenced by both
electronic and steric effects, and is rationalised very effectively by FMO theory [7].
In this context, NIs are considered to be “type II” dipoles, meaning that interactions
between both the HOMO of the dipole and the LUMO of the dipolarophile and the
interactions of the LUMO of the dipole and the HOMO of the dipolarophile may
have an impact on reaction rate [21]. Consequently, in the case of a truly type II NI
species, any form of substitution of the dipolarophile, electron-donating or electronwithdrawing, will increase reaction rate, with ethene proving to be the least reactive
39
to interact, due to more efficient overlap. This is in turn will favour one regioisomer
over the other. This original application of FMO suggested that 5-substituted
heterocycles were favoured in the majority of cases, with the sole exception of highly
electron-withdrawing groups preferentially yielding either regioisomeric mixtures or
4-substituted products [7].
While this technique is commonly used in the literature as a means to predict or
account for NI regioselectivity, it is far from universal and is in no way quantitative.
More recent approaches have emerged employing density functional theory (DFT)
as a tool with which to understand the regioselectivity of NI cycloadditions [10, 11].
The application of concepts such as hard-soft acid-base theory, molecular electron
density theory, relative electrophilicity and Fukui functions within these higher levels
of theory have enabled a much more accurate understanding of NI regioselectivity,
including quantitative predictions in some instances [12, 13].
However, despite these significant advances, regioselectivty in NI cycloadditions
remains difficult to predict or rationalise. While the vast majority of cases of monosubstituted alkenes and alkynes yield the 5-substituted product [14], numerous
exceptions exist to this trend, making the development of a general set of rules
challenging. While FMO [15, 16] and DFT [17, 18] calculations have both aided
in rationalising unexpected results, neither have demonstrated anything close to
absolute accuracy in their prediction methods.
One curious exception to the unpredictable regioselectivity of NI dipolarophiles
is the use of enamines as substrates. These species exhibit exclusive regioselectivity
for the 4-substituted pyrazoline product over the 5-substituted system, apparently
in contrast to the combined steric and electronic influences that direct most other
functional groups to the 5-position [3, 19]. This is discussed in more detail in
Sect. 3.2.8.
It has also been shown that NI regioselectivity can be influenced through the use
of a Lewis acid. Addition of scandium(III) triflate to the reaction mixture shown in
Scheme 3.2 was shown to yield the 4-substituted pyrazole products in a much higher
ratio than in the absence of the additive [20]. Unfortunately, this approach is limited
to substrates with coordinating functional groups, such as carbonyls, adjacent to both
the dipole and dipolarophile.
3.1.2 Rate of Reaction
The rate of reaction of NIs with dipolarophiles can be significantly influenced by both
electronic and steric effects, and is rationalised very effectively by FMO theory [7].
In this context, NIs are considered to be “type II” dipoles, meaning that interactions
between both the HOMO of the dipole and the LUMO of the dipolarophile and the
interactions of the LUMO of the dipole and the HOMO of the dipolarophile may
have an impact on reaction rate [21]. Consequently, in the case of a truly type II NI
species, any form of substitution of the dipolarophile, electron-donating or electronwithdrawing, will increase reaction rate, with ethene proving to be the least reactive