3.1 1,3-Dipolar Cycloaddition
43
The influence of entropy on the rate of cycloaddition should also be noted.
Competition experiments have determined that intramolecular cycloadditions
between NIs and electronically neutral alkenes have very similar reaction rates to
intermolecular cycloadditions with electronically activated alkenes [29]. This can be
rationalised by considering the highly ordered transition state of a cycloaddition
reaction, meaning that the high entropy penalty required for the intermolecular
process to occur cannot always be fully negated by the electronic activation of the
substrate.
When a reversible source of the dipole is used, the rate of NI generation can impact
the rate of cycloaddition. Studies have shown that when employing hydrazonyl
chlorides as a starting material, both increasing pH and decreasing concentration
of chloride ions can have a positive impact on reaction rate [30].
3.1.3 Carbon-Carbon Double Bonds
NIs were first shown to undergo 1,3-dipolar cycloaddition with alkenes by Huisgen
in his initial report, to yield the expected pyrazoline product from diphenyl NI and
dicyclopentene (Scheme 2.13) [31]. This scope was expanded considerably in 1962,
when Huisgen outlined the reactivity profiles of NIs with a comprehensive library
of dipolarophiles [1].
In the decades that have followed, numerous research groups have demonstrated
that 1,3-dipolar cycloaddition between NIs and alkenes is a facile and robust reaction
manifold, applicable to a broad palette of compounds. Examples range from relatively
unreactive unconjugated alkenes, [4, 29] through aryl and vinyl olefins, [2, 32, 33]
and to highly activated species such as α-β unsaturated carbonyls and vinyl sulfoxide
species (Scheme 3.5) [3, 34, 35]. One interesting point concerning the pyrazoline
generated through vinyl sulfoxide cycloaddition is that the sulfoxide may be oxidised
and spontaneously eliminate. This approach of NI-alkene cycloaddition followed by
elimination is a useful method of generating aromaticity through the preparation of
pyrazoles, assuming appropriate choice of dipolarophile [36].
While all of the examples discussed so far are intermolecular cycloadditions,
intramolecular reports are equally prevalent in the literature. Cyclisation between
an NI and an olefin attached to the same chemical scaffold was first exemplified by
Zecchi in 1977, 18 years after Huisgen’s initial report and 3 years after Zecchi himself
had performed the same reaction using an alkyne as the dipolarophile (Scheme 3.6)
[37, 38]. While more synthetically challenging to install both the dipolarophile
and dipole precursor within the same molecule, intramolecular cycloaddition has
multiple advantages over intermolecular cycloaddition. Depending to which end of
the dipole the “tether” is attached, the regioselectivity rules involved in intermolecular
examples may be overridden. Furthermore, cyclisation of a single molecule negates
the significant entropy penalty encountered by the dipole and dipolarophile during
the highly ordered transition state of a 1,3-dipolar cycloaddition. The result of this
is that unactivated dipolarophiles that may have otherwise required vast excesses or
43
The influence of entropy on the rate of cycloaddition should also be noted.
Competition experiments have determined that intramolecular cycloadditions
between NIs and electronically neutral alkenes have very similar reaction rates to
intermolecular cycloadditions with electronically activated alkenes [29]. This can be
rationalised by considering the highly ordered transition state of a cycloaddition
reaction, meaning that the high entropy penalty required for the intermolecular
process to occur cannot always be fully negated by the electronic activation of the
substrate.
When a reversible source of the dipole is used, the rate of NI generation can impact
the rate of cycloaddition. Studies have shown that when employing hydrazonyl
chlorides as a starting material, both increasing pH and decreasing concentration
of chloride ions can have a positive impact on reaction rate [30].
3.1.3 Carbon-Carbon Double Bonds
NIs were first shown to undergo 1,3-dipolar cycloaddition with alkenes by Huisgen
in his initial report, to yield the expected pyrazoline product from diphenyl NI and
dicyclopentene (Scheme 2.13) [31]. This scope was expanded considerably in 1962,
when Huisgen outlined the reactivity profiles of NIs with a comprehensive library
of dipolarophiles [1].
In the decades that have followed, numerous research groups have demonstrated
that 1,3-dipolar cycloaddition between NIs and alkenes is a facile and robust reaction
manifold, applicable to a broad palette of compounds. Examples range from relatively
unreactive unconjugated alkenes, [4, 29] through aryl and vinyl olefins, [2, 32, 33]
and to highly activated species such as α-β unsaturated carbonyls and vinyl sulfoxide
species (Scheme 3.5) [3, 34, 35]. One interesting point concerning the pyrazoline
generated through vinyl sulfoxide cycloaddition is that the sulfoxide may be oxidised
and spontaneously eliminate. This approach of NI-alkene cycloaddition followed by
elimination is a useful method of generating aromaticity through the preparation of
pyrazoles, assuming appropriate choice of dipolarophile [36].
While all of the examples discussed so far are intermolecular cycloadditions,
intramolecular reports are equally prevalent in the literature. Cyclisation between
an NI and an olefin attached to the same chemical scaffold was first exemplified by
Zecchi in 1977, 18 years after Huisgen’s initial report and 3 years after Zecchi himself
had performed the same reaction using an alkyne as the dipolarophile (Scheme 3.6)
[37, 38]. While more synthetically challenging to install both the dipolarophile
and dipole precursor within the same molecule, intramolecular cycloaddition has
multiple advantages over intermolecular cycloaddition. Depending to which end of
the dipole the “tether” is attached, the regioselectivity rules involved in intermolecular
examples may be overridden. Furthermore, cyclisation of a single molecule negates
the significant entropy penalty encountered by the dipole and dipolarophile during
the highly ordered transition state of a 1,3-dipolar cycloaddition. The result of this
is that unactivated dipolarophiles that may have otherwise required vast excesses or